Targeting persistently activated inflammatory microenvironment to promote chronic wound healing

The immune system plays a pivotal role in maintaining the balance of inflammatory responses and facilitating tissue repair and wound healing. However, under the combined influence of immune microenvironmental factors and external stimuli, immune cell dysfunction can lead to persistent activation of the inflammatory milieu, resulting in delayed or impaired wound healing. Therefore, regulating immune responses within the chronic inflammatory microenvironment and suppressing aberrant immune cell activation not only helps restore immune homeostasis but also effectively accelerates the wound healing process. Identifying and modulating novel targets associated with macrophage and T-cell dysregulation, as well as the crosstalk among immune cells, offers new insights and therapeutic strategies for the treatment of chronic inflammation-related disorders and wound repair. This review focuses on the molecular mechanisms underlying aberrant macrophage and T-cell activation, the intercellular crosstalk within the immune microenvironment, and their impact on the wound healing process. Furthermore, it highlights potential therapeutic targets for limiting persistent inflammation and re-establishing immune homeostasis. Elucidating these mechanisms and targets may provide promising avenues for the treatment of chronic inflammatory diseases and for advancing strategies in tissue repair and regeneration.

1 Introduction

Delayed healing and non-healing of chronic wounds represent a class of clinical problems driven by the persistent activation of the chronic inflammatory microenvironment, a process that involves multiple levels of immune regulation (1). The local inflammatory milieu plays a critical role in protecting the host against infection, repairing tissue damage, and maintaining systemic homeostasis. Effective interactions between immune cells and their specific ligands form the basis of immune function (2, 3). However, under the combined influence of the immune microenvironment and environmental stimuli, immune dysfunction may occur, leading to abnormal activation of the inflammatory milieu and thereby contributing to impaired or delayed wound healing (4, 5). Chronic non-healing wounds are typically characterized by sustained production of inflammatory mediators and cytokines, along with aberrant activation of macrophages and T cells. These abnormalities suppress the normal wound healing process, resulting in prolonged tissue damage and functional impairment (6).

During chronic wound healing, dysregulation of the immune system is one of the major causes of impaired or non-healing wounds (7, 8). Wound healing is classically divided into several overlapping phases, including inflammation, proliferation, and repair (9). Under physiological conditions, macrophages play a key role in the early inflammatory phase by clearing bacteria and cellular debris and by initiating tissue repair, whereas T cells are primarily involved in the subsequent adaptive immune response (10, 11). Macrophages are critical effector cells of the innate immune system that participate in pathogen recognition, antigen presentation, tissue repair, and the maintenance of immune homeostasis (12). A defining feature of macrophages is their high degree of plasticity, whereby they rapidly adjust their phenotype, metabolic state, and functional profile in response to distinct microenvironmental cues to meet the demands of inflammation, tissue remodeling, or homeostasis (13). This plasticity is not limited to the classical M1/M2 dichotomy, but rather reflects a dynamically regulated continuum of activation states, constituting a central regulatory hub in diverse pathological contexts such as chronic inflammation, the tumor microenvironment, and tissue regeneration. Accumulating evidence indicates that macrophages do not exist in fixed M1 or M2 states; instead, they exhibit a continuous and reversible spectrum of functional programs driven by various combinations of signals, including Interleukin-6 (IL-6)/Transforming Growth Factor-beta (TGF-β),Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)/Macrophage Colony-Stimulating Factor (M-CSF), lipid mediators, and hypoxic conditions (14, 15). For example, in the tumor microenvironment, tumor-associated macrophages (TAMs) can concomitantly express both M1 and M2 associated markers, whereas during wound repair, the transition from an M1-like to an M2-like phenotype is a critical step for resolution of inflammation and initiation of regeneration (16, 17). Failure of macrophages to switch effectively from a pro-inflammatory to a pro-reparative phenotype leads to sustained activation of M1-like macrophages, while aberrant interactions between dendritic cells (DCs) and T cells further drive persistent immune activation (18, 19). In particular, dysregulated activation of macrophages, T helper 1 (Th1) cells and T helper 17 (Th17) cells contributes to continuous delay of the wound healing process (20). Classically activated M1 macrophages promote inflammatory responses during the early stages of wound healing, whereas alternatively activated M2 macrophages exert anti-inflammatory and pro-repair functions during the later healing phase (21, 22). However, within a chronic inflammatory microenvironment, excessive activation of M1 macrophages results in a prolonged inflammatory state, suppresses the functions of M2 macrophages, and ultimately impedes the progression of wound healing (23, 24).

In addition, aberrant activation of Th1 and Th17 cells particularly under dysregulated control of the co-stimulatory molecule Inducible T-cell COStimulator (ICOS) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) further exacerbates immune imbalance and contributes to the non-healing state of chronic wounds (25, 26). In the context of the dysregulated immune microenvironment associated with impaired chronic wound healing, targeting the abnormal activation of immune cells and their receptors or downstream signaling pathways has emerged as a promising therapeutic strategy (27, 28). By modulating receptor function or intracellular signaling in immune cells, it is possible to effectively suppress pathological activation of macrophages, Th1 cells, and Th17 cells, thereby restoring immune homeostasis and promoting the normal progression of wound repair (29, 30). Targeting the aberrant crosstalk between macrophages and T cells and attenuating persistently activated inflammatory responses may represent a key approach to improving chronic wound healing outcomes (31, 32). Therefore, therapeutically modulating the persistently activated inflammatory microenvironment with a particular focus on regulating macrophage and T-cell function has become a potential new strategy for enhancing tissue repair and promoting the healing of chronic wounds.

2 Molecular mechanisms of normal wound healing

Wound healing is a complex, highly coordinated process involving multiple molecular mechanisms, which are generally divided into four major, overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Among these, the proliferative phase is a critical stage, primarily characterized by cell proliferation, angiogenesis, and extracellular matrix (ECM) remodeling (33, 34). During this phase, multiple molecular signaling pathways are engaged, and in particular, the regulatory mechanisms governing cell proliferation are essential for the subsequent progression of wound repair (9, 18).

2.1 Process of normal wound healing

When tissue injury occurs, the first response is hemostasis, which is achieved through vasoconstriction, platelet aggregation, and activation of coagulation factors. Platelets release a variety of growth factors, such as Platelet-Derived Growth Factor (PDGF), TGF-β, and Vascular endothelial growth factor (VEGF), all of which play important roles throughout the wound-healing process (35). The primary function of the inflammatory phase is to eliminate pathogens and remove damaged cells from the wound site. Innate immune cells, including neutrophils and macrophages, initiate the inflammatory response by secreting cytokines such as IL-1 and Tumor Necrosis Factor-alpha (TNF-α). These cytokines not only contribute to pathogen clearance but also provide essential signals for the transition to the proliferative phase (36). The hallmark of the proliferative phase is the proliferation of fibroblasts, epithelial cells, endothelial cells, and other cell types. Growth factors such as TGF-β, Epidermal Growth Factor (EGF) and Fibroblast Growth Factor (FGF) are key regulators of the proliferation of these cells. By binding to their cognate receptors on the cell surface, they activate downstream signaling pathways including Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K)-Akt, thereby promoting cell proliferation and migration (37). VEGF plays a pivotal role in angiogenesis during the proliferative phase. VEGF stimulates endothelial cell proliferation and migration, promoting the formation of new blood vessels and thereby supplying the wound area with oxygen and nutrients required for repair (38). ECM remodeling is another crucial component of the proliferative phase. Fibroblasts synthesize large amounts of ECM components, including collagen and elastin, and regulate ECM degradation and reconstruction via matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) (39, 40). During the remodeling phase, the structural organization of the wound gradually approaches that of normal tissue. Collagen fibers become more regularly aligned, and the tensile strength of the wound progressively increases. Fibroblasts further differentiate into myofibroblasts, which contribute to wound contraction and closure. The molecular mechanisms involved at this stage include regulation of fibroblast function by TGF-β, IL-10, and other mediators (41).

2.2 Influence of molecular mechanisms on the proliferative phase

Throughout wound healing, multiple signaling pathways act in a coordinated manner to promote cell proliferation and tissue repair. First, in terms of growth factor–receptor interactions, TGF-β plays a dual role in wound healing: it promotes cell proliferation while also regulating fibroblast migration and collagen synthesis. However, excessive TGF-β activation may lead to fibrosis and adversely affect the quality of wound repair (42). EGF and FGF promote the proliferation of keratinocytes and fibroblasts during the early stages of wound healing, thereby facilitating re-epithelialization and wound closure. EGF primarily enhances cell proliferation via activation of the Extracellular Signal-Regulated Kinase (ERK) signaling pathway, whereas FGF contributes to angiogenesis and ECM remodeling through activation of MAPK, PI3K/Akt, and other pathways (42, 43). Second, at the level of intracellular signaling, the PI3K/Akt pathway supports wound repair by promoting cell survival, proliferation, and migration. During the proliferative phase, Akt accelerates the healing process by enhancing the growth of fibroblasts and endothelial cells. The MAPK pathway is also crucial for cell proliferation, migration, differentiation, and stress responses, particularly in driving the proliferation of epithelial cells and fibroblasts after injury (44). Third, with regard to ECM remodeling, fibroblast activity during the proliferative phase is a key determinant of successful wound healing. MMPs mediate degradation of excessive or damaged ECM components, thereby facilitating the formation of new tissue. However, excessive matrix degradation or incomplete reconstruction can result in scar formation or hypertrophic scarring (45). Finally, immune cells also play an important role in this phase. Macrophages contribute to the proliferative phase by secreting cytokines such as TGF-β and IL-10, which promote fibroblast proliferation and collagen synthesis. In addition, macrophages assist wound repair by clearing necrotic cells and residual pathogens (46, 47).

Overall, the proliferative phase of wound healing is characterized by the convergence of multiple processes, including cell proliferation, angiogenesis, and ECM remodeling. Molecular mediators such as TGF-β, VEGF, EGF, and FGF exert crucial functions during this stage by regulating cell proliferation and migration, thereby driving wound repair and closure (48). The coordinated action of these mechanisms not only determines the efficiency of wound healing but also profoundly influences the final outcome, including scar formation and the overall quality of tissue repair.

3 Mechanisms of delayed or non-healing chronic wounds

One of the fundamental causes of delayed or non-healing chronic wounds is persistent activation of inflammation. Recent studies have shown that endogenous signals such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in the local wound environment, as well as immune cells and cytokines, act as “triggers” for sustained immune activation (49, 50). However, while many studies highlight the role of these factors in the persistence of inflammation, current research often overlooks their potential interactions and the specific mechanisms by which they contribute to chronic wound healing (Figure 1). PAMPs and DAMPs interact with immune cell surface receptors to activate downstream immune responses, maintaining a prolonged low-level inflammatory state that prevents the wound from transitioning smoothly from the inflammatory phase to the proliferative and remodeling phases, ultimately leading to tissue repair failure (49, 50). Notably, the delay in chronic wound healing is not merely a result of immune dysregulation but is a consequence of the intertwined effects of multiple biological pathways. These factors act through various cellular signaling pathways, collectively shaping the local immune response and creating a persistent inflammatory environment. While current research has elucidated some mechanisms, the synergistic effects of multiple pathways and their impact on chronic wounds remain underexplored.

Figure 1

Figure 1. Specific molecular mechanisms driving sustained activation in delayed or non-healing skin tissue. During infection, PAMPs such as LPS are recognized by PRRs on M1 macrophages and dendritic cells. In macrophages, ATP binds to the P2X7 receptor, leading to membrane depolarization and potassium ion efflux, which fully activates the NLRP3 inflammasome. ROS can also promote NLRP3 activation through oxidative modification and alteration of the intracellular environment. The activated NLRP3 inflammasome drives the release of IL-1β and IL-18, which are primarily secreted by M1 macrophages and act on IL-1β and IL-18 receptors through autocrine/paracrine signaling. This amplifies macrophage activation and prolongs the inflammatory phase. IL-1β and IL-18 also act on other immune cells, further exacerbating the local inflammatory response. Activated M1 macrophages secrete IFN-γ and IL-2, recruiting more immune cells to the wound, leading to sustained neutrophil infiltration, accumulation of proteases and ROS, matrix degradation, and disrupted angiogenesis, which inhibit the function of fibroblasts and keratinocytes, hindering reepithelialization. Gut microbiota dysbiosis allows LPS and SCFAs to cross the intestinal barrier and enter the bloodstream; at the wound site, TLR recognition promotes macrophage polarization toward the M1 phenotype and, through the “gut-skin/wound axis,” enhances the accumulation of MAIT cells, further disrupting the underlying microenvironment and causing delayed or non-healing. Chronic mechanical stress and other sterile injuries release DAMPs (such as HMGB1, ATP), which bind to PRRs on dendritic cells and macrophages, inducing macrophages to express IL-23 and IL-17. IL-12 and IFN-γ drive CD4⁺ T cell differentiation into Th1 cells, further activating macrophages, weakening the suppressive effects of Treg cells, and activating CD8⁺ T cells. This leads to further damage of epithelial cells and fibroblasts at the wound edge, disrupting immune tolerance and repair rhythms. Macrophage-derived IL-23 promotes Th17 cell differentiation, and the key effector molecule IL-17A upregulates COX-2, maintaining PGE₂ production. This results in vasodilation and leakage, enhancing macrophage recruitment/activation, amplifying the protease/antiprotease imbalance, and increasing oxidative stress. These processes consume growth factors, damage the extracellular matrix and granulation tissue quality, and ultimately lock the wound in a persistent inflammatory state, leading to delayed or non-healing.

3.1 Overactivation of inflammatory cells

Normal inflammation is a short-term and controlled physiological process aimed at clearing pathogens and necrotic tissue, thereby creating favorable conditions for subsequent repair. However, in chronic wounds, the inflammatory response often persists for extended periods, leading to prolonged infiltration and overactivation of neutrophils and macrophages. These cells continuously release pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6, thereby exacerbating local inflammation (51, 52). This persistent immune response not only disrupts the wound healing process but also causes continuous damage to the local tissue. Excessive inflammation first manifests as apoptosis and tissue necrosis (53). The over-release of inflammatory mediators induces apoptosis in normal cells at the wound site, such as fibroblasts and endothelial cells, thereby inhibiting their proliferation and migration and further hindering wound repair (36, 54) Additionally, the sustained activation of immune cells leads to their prolonged accumulation at the wound site, depleting the resources necessary for repair. This accumulation may also result in secondary damage to already-repaired tissue, intensifying the vicious cycle of chronic inflammation.

Chronic wound inflammation is closely associated with dysfunctional macrophage activity and excessive activation of the NOD-like Receptor Family Pyrin Domain-Containing 3 (NLRP3) inflammasome in innate immunity (55). The interaction between PAMPs and pattern recognition receptors (PRRs) is considered a key driver in maintaining the active inflammatory state within the microenvironment (56). As such, strategies targeting macrophage polarization and NLRP3 inflammasome activation are becoming a major focus of chronic wound treatment research. At the wound site, bacterial lipopolysaccharides (LPS), viral double-stranded RNA, and other PAMPs can be recognized by Toll-like receptors (TLRs) and NOD-like receptors (NLRs) on macrophages and dendritic cells. This activates the Nuclear Factor kappa-B(NF-κB) and Interferon Regulatory Factor 3 (IRF3) signaling pathways, inducing the expression and release of pro-inflammatory cytokines such as pro-IL-1β, TNF-α, and IL-18 (57, 58). IL-1β and IL-18 further promote the polarization of monocytes to M1 macrophages through autocrine and paracrine signaling, amplifying the inflammatory response (59).

M1 macrophages are one of the primary effector cells of the NLRP3 inflammasome. On top of the initial PAMPs-PRRs signaling, DAMPs such as ATP, reactive oxygen species (ROS), uric acid crystals, and cholesterol crystals further trigger the assembly and full activation of the NLRP3 inflammasome (60, 61). For example, large amounts of ATP released by damaged cells induce potassium ion efflux via the P2X7 receptor, leading to a decrease in intracellular potassium concentrations, which subsequently drives NLRP3 inflammasome activation (62). Simultaneously, ROS plays a crucial regulatory role, potentially promoting the amplification of inflammation by oxidatively modifying key molecules or altering the cellular redox environment. Therefore, strategies targeting P2X7 receptor antagonists or inhibiting ROS production are considered promising for improving chronic wound healing and are being tested in clinical trials to verify their efficacy (63). The activation of the NLRP3 inflammasome results in the conversion of pro-caspase-1 to active caspase-1, which then cleaves pro-IL-1β and pro-IL-18 into their mature forms and releases them (64, 65). These effector molecules not only directly exacerbate inflammation but also enhance M1 macrophage polarization, forming a self-amplifying inflammatory positive feedback loop. This loop drives the continuous release of ATP, ROS, and other molecules into the tissue microenvironment, further activating PRRs and maintaining a persistent “TLR4/macrophage/NLRP3” inflammatory axis. The outcome is tissue necrosis and impaired repair, keeping the wound trapped in the inflammatory phase and preventing progression to the healing phase (66, 67).

While research in this field has provided important insights into the immunological mechanisms of chronic wounds, some studies still have limitations. First, although existing studies have demonstrated the pivotal role of the NLRP3 inflammasome in chronic wound inflammation, the specific molecular mechanisms remain incompletely understood. Many studies focus on isolated mechanisms or molecules, lacking a systematic analysis of their interactions (68). Therefore, more research is needed to unravel the complex interplay between these cytokines and signaling pathways (69). Second, while studies on targeting P2X7 receptors or ROS inhibitors in chronic wound therapy have strong preclinical evidence, the success rate of clinical trials remains low. Some trials suffer from small sample sizes and design flaws, leading to inconclusive results and requiring further verification (70, 71). As such, future research should not only strengthen in-depth analysis in basic research but also focus more on optimizing the design of clinical studies to ensure the efficacy and safety of new therapies.

3.2 Abnormal activation of APCs maintains the inflammatory environment of chronic wounds

During normal tissue repair, Regulatory T cells (T_Reg) constrain excessive activation of Th cells and cytotoxic T lymphocytes (CTLs) to maintain immune homeostasis and a controllable, self-limited inflammatory phase. Mechanistically, T_Reg cells highly express CTLA-4, which binds B7 molecules (CD80/CD86) on antigen-presenting cells (APCs) and competitively inhibits CD28-mediated co-stimulation (72, 73). A process essential for timely resolution of early wound inflammation. In parallel, Programmed Death-Ligand 1 (PD-L1) on T cells engages PD-L1/PD-L2 on APCs to deliver inhibitory signals that further restrict T cell activity (74, 75). T_Reg -derived IL-10 and TGF-β, together with arginase-1 (ARG1) and inducible nitric oxide synthase (iNOS) from myeloid-derived suppressor cells (MDSCs), suppress effector T-cell overactivation (76, 77). In addition, the CD39/CD73 ectonucleotidase pathway on APCs generates adenosine, which signals through A2A receptors to dampen T-cell function. Collectively, these checkpoints terminate inflammation at an appropriate level and permit progression into tissue repair and remodeling.

In chronic wound settings, however, persistent pathogen products and necrotic tissue components drive presentation of aberrant antigens, breaking immune tolerance and sustaining long-lived activation of APCs and CTLs. Activated APCs continuously stimulate CD4⁺ and CD8⁺ T cells via MHC class II and cross-presentation, and their heightened expression of CD80/CD86 strengthens CD28-dependent co-stimulation, creating a self-reinforcing activation loop (78, 79). Concomitantly, APC-derived TNF-α, IFN-γ, IL-12, and IL-2 promote differentiation of naïve Th0 cells into Th1, Th2, and Th17 subsets, amplifying both cytotoxic and humoral responses (80, 81). Th2 expressed CD40L engages CD40 on B cells, driving robust antibody production and immune complex deposition. These immune complexes are continuously taken up and processed by APCs, sustaining cytokine release and local tissue injury and establishing a hard-to-break positive feedback loop that directly contributes to delayed or non-healing wounds (82, 83). Although CTLA-4 is often transiently upregulated on activated Th1/Th2/Th17 cells and CTLs to restrain responses, this inhibitory pathway is frequently inadequate or dysfunctional in chronic wounds, permitting persistently hyperactive effector T cells that damage tissue (84, 85). Ongoing antigenic stimulation and autoreactive antibodies secreted by plasma cells further augment immune complex formation, exacerbating local necrosis, fibrosis, and microvascular injury and thereby suppressing effective angiogenesis and fibroblast-mediated repair (86, 87). In parallel, macrophages skew toward an M1 phenotype under sustained exposure to IFN-γ and TNF-α, producing excessive inflammatory mediators and ROS, which impedes M2-driven tissue reconstruction and neovascularization (88, 89).

Thus, aberrant activation of APCs together with dysregulated T-cell responses in chronic wounds not only prolongs the inflammatory phase but also blocks the initiation of repair, culminating in an “immune–inflammation lock-in” state. Therapeutically, epigenetic attenuation of excessive CD80/CD86–CD28 interactions or enhancement of negative checkpoints such as CTLA-4 and PD-1 may restore T-cell tolerance and reduce immunopathology (90, 91). Concurrent strategies that redirect macrophage polarization (inhibiting M1, promoting M2) and temper overactive Th1/Th17 responses hold promise for rebalancing the local immune microenvironment, enabling transition from persistent inflammation to tissue repair and ultimately improving chronic wound healing outcomes (92).

Despite current research highlighting various immune regulatory mechanisms in wound healing, these mechanisms are often interwoven and complex. For instance, although CTLA-4 plays a crucial inhibitory role in normal immune responses, its dysregulation in the chronic wound environment may exacerbate immune imbalance (25, 93). Therefore, future studies should further investigate the specific mechanisms underlying CTLA-4 dysfunction in chronic wound healing to better understand its therapeutic potential. While molecules such as IL-10 and TGF-β are key players in the immune regulatory functions of T_Reg cells, their dual roles in chronic inflammation—where they can both suppress immune responses and potentially promote fibrosis—highlight the need for more research into their precise mechanisms (94, 95). The roles of these factors may vary across different stages of wound healing, and further studies are necessary to elucidate their specific functions within the local immune environment. Regarding the regulation of macrophage polarization, current research primarily focuses on accelerating wound healing by inhibiting M1 macrophages or promoting M2 macrophage polarization. However, whether macrophage polarization is a singular target or if there are additional subtypes and regulatory pathways yet to be identified remains to be experimentally verified. Further investigation is needed to determine the broader scope of macrophage polarization and its potential impact on chronic wound healing.

3.3 Metabolic and oxidative stress imbalance

3.3.1 Imbalance of oxidative stress responses

Persistent inflammation is usually accompanied by high levels of oxidative stress and metabolic dysregulation, which together aggravate cellular damage and profoundly impair normal healing. Continuous generation of free radicals and ROS is a major driving force of cellular injury, further amplifying local inflammation and tissue destruction and thereby suppressing the repair process (96). However, although the detrimental role of free radicals and ROS in cellular damage is widely recognized, some studies have suggested that ROS at low concentrations may exert beneficial effects on cellular repair (97, 98). In addition, sustained inflammatory responses disrupt normal metabolic processes within the wound area, leading to insufficient cellular energy supply. The activity of reparative cells, such as fibroblasts and endothelial cells, declines, which further compromises tissue repair capacity and worsens the healing status of chronic wounds (99). This controversy highlights the dual role of ROS in cellular physiology and underscores the need for more refined, concentration-dependent analyses when investigating their functions.

Persistent oxidative stress impairs cell membranes, DNA, and protein structures, thereby inhibiting cellular proliferation and migration and delaying the course of wound repair (100, 101). It is noteworthy, however, that most existing studies on oxidative stress and wound healing have focused on acute wounds, and there is still no consensus regarding its impact on chronic wounds. This discrepancy may be related to the fact that the long-term microenvironment of chronic wounds differs substantially from that of acute injuries. Future studies should pay greater attention to this distinction in order to elucidate the specific roles of oxidative stress in chronic wound healing (102, 103).

Moreover, sustained inflammation disrupts normal metabolic processes in the wound region, resulting in inadequate energy supply to cells. The reduced activity of reparative cells, including fibroblasts and endothelial cells, further weakens tissue repair capacity and aggravates poor healing in chronic wounds (104, 105). Although this viewpoint is supported by multiple studies, other reports indicate that the decline in reparative cell activity may not be solely attributable to energy deficiency, but is also closely linked to alterations in intracellular signaling pathways (106). Dysregulation of these pathways may play an important role in the wound healing process, suggesting that therapeutic strategies should take into account multidimensional cellular and molecular mechanisms.

3.3.2 Gut microbiota and metabolic imbalance

Dysbiosis of the gut microbiota is closely associated with the pathogenesis of delayed and non-healing chronic wounds. Studies have shown that patients with hard-to-heal chronic wounds often exhibit marked alterations in gut microbial composition, accompanied by impaired intestinal barrier function, leading to a “leaky gut” phenotype. Increased intestinal permeability allows microorganisms and their derived molecules (such as LPS) to translocate across the intestinal wall, enter the circulation, and reach the wound site, where they are recognized by pattern recognition receptors (e.g., TLRs) expressed on locally enriched macrophages and dendritic cells. This aberrant activation of immune cells further amplifies inflammatory responses and aggravates tissue damage (107, 108). Consequently, gut microbiota dysbiosis and disruption of the intestinal barrier jointly drive the persistence of inflammatory responses and the delay of tissue repair in chronic wounds. Although this process is supported by experimental data, the prevalence and precise mechanisms of “leaky gut” across different individuals remain a matter of debate. Some studies suggest that whether gut dysbiosis directly causes delayed chronic wound healing still requires confirmation in larger, well-designed clinical trials.

Another hallmark of gut microbiota dysbiosis is reduced levels of short-chain fatty acids (SCFAs) (109). SCFAs are known to enhance the expression of Phosphatase and Tensin homolog (PTEN), which in turn restricts excessive inflammatory activation by inhibiting the PI3K-Akt signaling pathway (110, 111). Insufficient SCFA availability disrupts this regulatory mechanism, leading to abnormal M1 macrophage polarization and heightened pro-inflammatory activity, thereby further impairing wound healing (112). Simultaneously, SCFA deficiency compromises T-cell regulatory functions, driving excessive activation of effector subsets such as Th1 and Th17 cells, which release large amounts of IFN-γ and IL-17. These cytokines intensify local immune responses and tissue injury (113). The combined abnormal activation of macrophages and T cells establishes a self-perpetuating inflammatory–immune feedback loop that represents a key pathological barrier to wound resolution. In addition to SCFAs, other gut microbiota-derived metabolites (e.g., serotonin) and circulating inflammatory cytokines (e.g., IL-6, TNF-α) modulate peripheral immune homeostasis and indirectly influence cutaneous wound repair (114, 115). Notably, mucosal-associated invariant T (MAIT) cells of gut origin have been found enriched within chronic wound tissues. These cells secrete abundant pro-inflammatory mediators, including IFN-γ, TNF-α, and IL-17, which suppress fibroblast activity and angiogenesis, thereby further impeding tissue regeneration. Thus, therapeutic strategies aimed at restoring gut microbiota composition and metabolite production (e.g., SCFAs and serotonin) to reestablish the balance of M1 macrophage and T-cell activity are considered promising approaches for enhancing chronic wound healing (116, 117).

Accordingly, targeting the sustained activation of the inflammatory microenvironment in chronic wounds—particularly by inhibiting aberrant M1 macrophage polarization, limiting overactivation of Th1/Th17 subsets, and enhancing T_Reg -mediated immunosuppressive functions—may help reestablish immune homeostasis and promote tissue repair (118, 119). Although classical anti-inflammatory agents such as TNF-α inhibitors have already been applied, challenges remain in improving tissue specificity while maintaining the physiological immune functions of macrophages and T cells (120–122). Therefore, identifying more precise immunomodulatory targets holds significant potential for advancing novel therapeutic strategies in chronic wound repair and regeneration.

3.4 Immune dysregulation and immune escape in chronic wound healing impairment

During normal wound healing, the immune system precisely modulates the intensity of the inflammatory response and terminates inflammation at an appropriate time (123). However, under conditions of persistent inflammation, immune regulatory mechanisms become dysregulated, and pro-inflammatory cytokines such as IL-1 and IL-6 remain continuously elevated. As a result, the immune response fails to transition in a timely manner from a pro-inflammatory to a reparative state, thereby delaying the healing process (124). Prolonged inflammation may lead to an “overreaction” of the immune system, creating a vicious cycle in which immune cells not only target pathogens but also attack healthy tissues, damaging already repaired structures (68, 125). Although this excessive immune response is widely regarded as a key factor in chronic wound healing impairment, some studies suggest that, in specific contexts, abnormal immune cell activation may not simply represent an “overreaction,” but may instead be closely associated with mechanisms of immune escape (126). Such immune escape may prevent the immune system from effectively clearing local microorganisms or damaged tissue, thereby prolonging the healing process, although its precise molecular mechanisms remain incompletely understood (125). In addition, prolonged exposure of the immune system to a chronic inflammatory milieu may induce a state of “tolerance,” resulting in a marked reduction in immune efficiency and failure to adequately eliminate residual infection or repair tissue damage (127, 128). While this concept is widely supported by multiple studies, other reports indicate that the development of immune tolerance is not the sole contributing factor, and that the interplay and alternation between tolerance and immune escape in chronic inflammation require further distinction and in-depth investigation.

Recent studies indicate that delayed or non-healing chronic wounds are strongly associated with dysregulated adaptive immune responses, particularly the imbalance between effector T cells and T_Reg. DAMPs, endogenous signals released from injured or necrotic cells, are normally confined to intracellular compartments under physiological conditions. Upon tissue injury, however, DAMPs are released into the extracellular space and activate inflammatory signaling pathways, representing a critical mechanism underlying persistent inflammatory activation and impaired tissue repair in chronic wounds (49, 129). Under normal circumstances, injury-induced stress responses are self-limiting, facilitating macrophage phenotype switching and controlled T-cell activation to promote repair and regeneration. Once the stress resolves, tissue homeostasis is restored (130, 131). In chronic wounds, by contrast, prolonged and amplified stress responses disrupt the balance between effector T cells and T_Reg, compromise immune tolerance, and sustain chronic inflammation that hinders healing.

When cells are damaged, DAMPs such as high-mobility group box 1 (HMGB1), heat shock proteins (HSPs), ATP, and uric acid are released extracellularly. Elevated circulating DAMPs engage PRRs on dendritic cells and macrophages, thereby activating innate immunity and inducing the secretion of inflammatory mediators including IL-23, IL-17, IL-12, and IL-2 (58, 132). IL-12 and IFN-γ promote CD4⁺ T-cell differentiation toward the Th1 phenotype, while Th1-derived IFN-γ further activates M1 macrophages, reinforcing Th1 responses and suppressing the immunosuppressive function of T_Reg (118, 133). This persistent positive feedback loop undermines immune tolerance and sustains a highly pro-inflammatory environment detrimental to wound repair. In chronic wound models, hyperactive Th1 responses and continuous M1 macrophage accumulation are regarded as major barriers to healing (134, 135). Meanwhile, IL-23 and prostaglandin E2 (PGE2) promote Th17, group 3 innate lymphoid cell (ILC3), and γδ T-cell activation, leading to excessive production of IL-17A. IL-17 stimulates epithelial cells, endothelial cells, and fibroblasts to secrete IL-6 and TNF-α, driving the persistent recruitment and aberrant activation of neutrophils and macrophages (136, 137). Overexpression of IL-23 and expansion of Th17 cells further impair T_Reg function, aggravating immune imbalance and establishing an irreversible inflammatory state (138). This dysregulation not only disrupts the immune homeostasis required for wound repair but also impedes normal regeneration of fibroblasts and keratinocytes (139).

IL-17A also enhances cyclooxygenase-2 (COX-2)-dependent synthesis of the pro-inflammatory lipid mediator PGE2. Activation of COX-2 and PGE2 promotes vasodilation and leukocyte extravasation, while simultaneously amplifying Th17 activation, thus establishing a positive feedback loop for IL-17A (140, 141). The hyperactive IL-23/IL-17 axis contributes to excessive cytokine deposition within the wound microenvironment, locking the tissue in the inflammatory phase and preventing transition to the proliferative and remodeling phases. Persistent inflammation further induces continuous DAMP release, perpetuating a vicious “injury–inflammation–reinjury” cycle. Accordingly, targeting IL-17 and IL-23—either through specific neutralizing antibodies or in combination with nonsteroidal anti-inflammatory drugs to block the IL-23/IL-17 axis and COX-2 signaling—represents a potential strategy to alleviate chronic wound inflammation (142, 143). In parallel, promoting macrophage repolarization from M1 to M2 phenotypes, restoring T_Reg -mediated immunosuppression, and appropriately activating Th2-associated repair pathways could reestablish immune balance, thereby facilitating angiogenesis, cell proliferation, and tissue remodeling to ultimately promote wound healing.

3.5 Fibrosis and excessive extracellular matrix synthesis leading to limited angiogenesis

Fibrosis is a process in which tissue repair mechanisms become imbalanced due to repeated injury or chronic inflammation. It is characterized by the excessive accumulation of ECM components, such as collagen, fibronectin, and basement membrane proteins, produced by activated fibroblasts/myofibroblasts. This excess ECM replaces normal tissue structure, leading to tissue stiffening and functional loss (144, 145). During fibrosis, significant changes occur in the mechanical properties of the ECM. For instance, fibrotic ECM exhibits thickened fibers, linearization of collagen fibers, increased cross-linking, and thickening of the basement membrane (146). These changes create a “fibrotic microenvironment,” where the ECM is no longer just a passive structural support but becomes an active “cell regulator” (matrisome) (147, 148). As a result, excessive or abnormal ECM remodeling in chronic wounds or organ fibrosis severely impedes normal angiogenesis during wound healing or tissue repair.

In chronic wounds and organ fibrosis, the excessive deposition and cross-linking of collagen fibers make the ECM stiffer and less deformable. The process of angiogenesis, which involves endothelial cell migration, lumen formation, and basement membrane remodeling, relies on a pliable and elastic ECM scaffold (149). When the ECM becomes too stiff, it inhibits endothelial cell migration and spreading, as cells find it difficult to mechanically sense and compress their way into the matrix. Moreover, a stiffer ECM activates mechanosensitive signaling pathways such as YAP/TAZ, which perpetuate fibroblast activation and lead to the formation of contractile fibrous structures. These structures further compress the space available for angiogenesis. In fibrotic areas, excessive ECM leads to reduced intercellular spacing, ECM thickening, and alterations in the interface between the basement membrane and interstitial matrix, making it difficult for endothelial cells to penetrate or form new capillary beds. Additionally, excessive ECM synthesis often goes hand-in-hand with the persistent activation of pro-fibrotic factors, such as TGF-β, which not only promotes ECM deposition but may also suppress angiogenesis (150). For instance, TGF-β can inhibit endothelial cell proliferation or induce a non-angiogenic state in endothelial cells under certain conditions. ECM itself can bind and store angiogenesis-related growth factors such as VEGF and FGF, but in a fibrotic environment, the release of these factors may be limited (147). High cross-linking of the ECM suppresses the activity of MMPs, enzymes responsible for basement membrane degradation, or stabilizes the ECM structure to the point where it becomes resistant to degradation, thus preventing endothelial cells from forming lumens (151) At the same time, fibrotic regions are often associated with hypoxia or low perfusion, which typically stimulates angiogenesis. However, in highly fibrotic ECM, hypoxia-induced angiogenic signals, such as HIF1α, activate VEGF, which may be “blunted” by mechanical and structural barriers, leading to a weakened angiogenic response (152, 153). Once angiogenesis is impaired, tissue perfusion declines, and the supply of oxygen and nutrients is limited. This, in turn, impacts the cellular metabolism needed for angiogenesis, such as the metabolism of endothelial cells, fibroblasts, and surrounding support cells (154). The decline in mitochondrial function and the increase in ROS, compounded by elevated ECM stiffness, make it difficult for newly formed blood vessels to remain stable (155). Therefore, the “microvascular sparsity and dysfunction” characteristic of fibrotic areas further inhibits vascular regeneration, aggravates tissue ischemia, and impairs tissue repair and remodeling. Recent studies have shown that increased ECM stiffness can activate fibrotic signaling pathways within endothelial cells or surrounding support cells via integrin-dependent mechanisms, indirectly suppressing angiogenesis (156, 157) While much of the research in chronic wound healing has focused on inflammation and immune mechanisms, the changes in ECM density and stiffness caused by fibrosis have also been recognized as key factors in “microvascular generation failure.” Some studies suggest that antifibrotic strategies, such as inhibiting collagen cross-linking or modulating the activity of basement membrane-degrading enzymes, could be new approaches to promoting angiogenesis.

Thus, the excessive synthesis of ECM in fibrosis leading to restricted angiogenesis is a multifaceted process. From mechanical barriers and biochemical microenvironment changes to endothelial cell dysfunction and limited vascular space, as well as metabolic-perfusion deterioration, these factors all contribute to the significant inhibition of new vessel formation. To overcome the problem of delayed microvascular reconstruction in chronic wounds and organ fibrosis, it is necessary not only to regulate immune and inflammatory responses but also to focus on the structural and functional repair of the ECM.

4 Biology of inflammation resolution and therapeutic strategies for promoting resolution in chronic wound healing and non-healing delayed wounds

Traditional “anti-inflammatory” approaches primarily focus on inhibiting the inflammatory response itself. In contrast, the biology of inflammation resolution emphasizes that inflammation has an actively programmed “termination mechanism.” Inflammation resolution does not rely on the passive depletion of inflammatory mediators but rather on an actively initiated resolution program. This program’s core tasks include halting the sustained recruitment of granulocytes, clearing dead/damaged cells and necrotic debris, repairing and reconstructing barriers and organ functions, while avoiding an increased susceptibility to infections caused by excessive immune suppression (158, 159). One molecular hallmark of this process is the “lipid mediator switch,” where pro-inflammatory mediators such as prostaglandins and leukotrienes are replaced by specialized pro-resolving mediators (SPMs). These SPMs drive the resolution program without compromising host defense capacity (160, 161). Based on this theory, therapeutic strategies aimed at enhancing immune cell efferocytosis, utilizing IL-10/TGF-β in a context-dependent manner, and targeting key inflammatory pathways can serve as important approaches to treat chronic inflammation and difficult-to-heal wounds.

4.1 Direct enhancement of efferocytosis

In various chronic inflammatory diseases, such as atherosclerosis, chronic obstructive pulmonary disease, and inflammatory bowel disease, the clearance of apoptotic neutrophils and foam cells is often impaired. Failure of efferocytosis leads to the expansion of necrotic cores, continued neutrophil infiltration, and compromised repair quality (162, 163). Efficient efferocytosis not only terminates the inflammatory response but also triggers the generation of SPMs, acting as a “final gate” for the resolution of inflammation (164). Therefore, “direct enhancement of efferocytosis” forms a critical foundation for resolution-promoting therapies.

First, efferocytosis can be promoted by releasing “don’t eat me” signals to remove checkpoint inhibition, such as blocking the CD47–SIRPα axis. In a mouse model of atherosclerosis, anti-CD47 antibodies restored efferocytosis within plaques, reduced necrotic core size, and alleviated lesions. The underlying mechanism is closely related to the regulation of the TNF-α–ADAM17 axis (165, 166). CD47–SIRPα-targeting drugs, such as magrolimab and various SIRPα antibodies, have entered multiple clinical trials in oncology; however, known safety risks such as anemia and thrombocytopenia have been identified. The clinical validation of these therapies in chronic injury tissue repair is lacking, indicating that their translation to non-cancer inflammation areas requires careful assessment of the potential benefits and risks (167, 168).

Second, direct activation of phagocytic receptors and their signaling pathways can amplify the efferocytosis response. MerTK, a key phagocytic receptor, enhances macrophage ability to engulf apoptotic cells and promotes SPM synthesis through the nuclear translocation of 5-LOX (169, 170). Studies have shown that MerTK agonistic antibodies have anti-pain and tissue repair-promoting effects in a neuropathic pain animal model, suggesting their cross-organ potential for promoting resolution (171). Further development of TAM receptor-ligand engineering, such as Gas6/Protein S and integrin pathway modulation, could enhance the recognition and engulfment of “Eat-me” signals via biased activation of ligands or antibodies (172). However, it is important to note that excessive Axl activation may promote inflammation or cell migration in certain contexts. Therefore, selective regulation favoring MerTK is preferred (173, 174). Additionally, inhibiting ADAM17/ADAM10-mediated MerTK shedding and maintaining its “grabber” function at the cell surface, or reducing TNF-α stress burden, may help stabilize efferocytosis ability (175, 176).

Third, optimizing the clearance of apoptotic cells by enhancing the recognition and bridging of “Eat-me” signals is another strategy. Recombinant MFG-E8 (lactadherin) can bridge phosphatidylserine (PS) and α_vβ_3/α_vβ_5 integrins, showing potential in preclinical studies of primate periodontal inflammation models, where it inhibits inflammation and preserves bone mass. It is considered a promising local agent for promoting inflammation resolution and wound healing (177).

Overall, direct enhancement of efferocytosis in inflammatory diseases and chronic inflammatory damage is still in the early stages of research. Its organ-specific context dependence and optimal intervention windows need further clarification. When the focus is on clearing large numbers of apoptotic or senescent cells rather than attacking viable tissue cells, de-repression and amplification of efferocytosis can be particularly effective. The key scientific challenge for the clinical application of resolution-promoting therapies is achieving precise and spatiotemporally specific enhancement of efferocytosis without compromising the host’s defense against infection.

4.2 Lipid mediator class switch

In the early stages of acute inflammation, pro-inflammatory mediators such as prostaglandins and leukotrienes (e.g., PGE₂, PGD₂, LTB₄) dominate the response. Subsequently, through a programmed “class switch,” the production shifts to specialized SPMs, including lipoxins, resolvins (D/E/n-3 DPA series), protectins, and maresins (159, 178, 179). This transition marks the initiation of the active resolution phase of inflammation, during which granulocyte recruitment is terminated, macrophage efferocytosis is enhanced, and tissue repair and functional reconstruction are activated—rather than the passive “extinction” of inflammation.

In various chronic inflammatory conditions, insufficient production of SPMs, downregulated receptor expression, or impaired intercellular synthesis can lead to a failure of the pro-inflammatory to pro-resolving class switch, resulting in the persistence of chronic inflammation (163). In diseases of the respiratory system, cardiovascular conditions, and immune dysregulation/autoinflammatory diseases, low levels of SPMs or disruption of this “class switch” have been closely linked to increased disease activity and ongoing tissue damage (180).

SPMs initiate a comprehensive resolution program through specific G-protein-coupled receptors such as ALX/FPR2, ChemR23, GPR32, and GPR18, while maintaining the host’s defense capabilities against pathogens (181). This provides a theoretical basis for “supplementing post-switch products,” which can be achieved either by directly supplementing or mimicking SPM analogs, stable derivatives, or through localized delivery systems such as ocular, oral, or pulmonary formulations. In animal models of acute inflammation, low-dose SPM regimens have been shown to significantly shorten the time to inflammation resolution (182). Research on lipid-based resolution mediators has now entered early clinical stages. For example, the novel lipid-derived endogenous molecule RX-10045 (a steroid) has shown good safety in dry eye disease and some efficacy signals, but it has not yet progressed to Phase III clinical trials, indicating that the dosing regimen and pharmacokinetics still require optimization (183). Annexin A1 and its short peptide Ac2–26 exert pro-resolution effects via the ALX/FPR2 receptor, demonstrating protective effects in models of cardiovascular injury and infection, and are actively being evaluated (184). These endogenous resolution pathways can also complement n-3 polyunsaturated fatty acids, which can enhance the levels of SPM precursors and certain SPMs in the body, offering potential to reduce the immunosuppressive side effects of traditional anti-inflammatory drugs while accelerating functional recovery (185, 186).

Overall, the “class switch” of lipid mediators represents a transition from inflammation’s “ignition” phase to “extinguishing and repair.” The success or failure of this switch directly determines whether inflammation can resolve effectively and with high quality. Future pro-resolving therapeutic strategies could involve the use of SPM substitutes/analogs, aspirin- or statin-induced R-pathway activation, enhanced 15-LOX activity, and intercellular synthesis capacity, combined with precursor supplementation and precise local delivery. This approach would transform the intrinsic resolution program into a controllable therapeutic lever. It is important to note that simply inhibiting prostaglandins does not equate to promoting resolution; only when applied at the right time, dose, and target, and combined with quantifiable SPM levels and temporal markers, can “class switch” be effectively controlled and clinically validated.

4.3 Targeting inhibition of TLR

The primary function of TLRs is to recognize PAMPs or DAMPs, thereby initiating the innate immune response. In macrophages, TLR signaling preferentially induces the M1 phenotype, promoting high expression of iNOS, TNF-α, IL-6, and IL-1β (187, 188). Furthermore, TLR activation of the NLRP3 inflammasome results in the production of large amounts of IL-1β. IL-1β, through autocrine and paracrine signaling, sustains the M1 phenotype, enhancing glycolytic metabolism and NF-κB signaling activity (189, 190). This persistent pro-inflammatory metabolic state restricts the conversion of macrophages to the M2 phenotype, prolonging the inflammatory process in tissues. In contrast, M2 macrophages are characterized by the secretion of IL-10 and TGF-β and are primarily involved in tissue repair and immune suppression. However, continuous activation of the TLR-NLRP3 pathway can inhibit STAT6 and PPARγ signaling, disrupting the IL-4/IL-13-mediated M2 polarization process. Additionally, IL-1β and IL-18, by promoting IFN-γ and IL-17 production, indirectly hinder the maintenance of the M2 phenotype (188, 189). These mechanisms collectively result in the prolonged dominance of pro-inflammatory M1 macrophages within the immune microenvironment, sustaining the inflammatory response.

TLRs play indispensable roles in innate immunity and the inflammatory response during delayed or non-healing chronic wounds; however, the fine-tuned regulatory mechanisms governing their signaling remain incompletely defined (191, 192). Recent work identifies Cullin 4B (CUL4B), a component of the CUL4B–RING E3 ubiquitin ligase complex, as an intrinsic negative regulator of TLR-triggered inflammation. Loss of CUL4B in macrophages markedly elevates pro-inflammatory mediators (TNF-α, IFN-γ, IL-12, IL-2) while reducing anti-inflammatory factors (TNF-β, IL-10), thereby potentiating inflammation downstream of TLR3, TLR4, or TLR2 stimulation (193). This sustained inflammatory state directly impedes wound repair (Table 1).

Table 1

Table 1. Regulatory targets for restoring immune homeostasis, signaling pathways, biological benefits, and preclinical/clinical trials.

Augmented TLR-induced inflammation is closely linked to increased glycogen synthase kinase-3β (GSK3β) activity. GSK3β supports prolonged survival and activation of macrophages and lymphocytes, extending the local inflammatory phase and hindering granulation and re-epithelialization (194, 195). The small-molecule inhibitor CHIR99021 binds the ATP site of GSK-3 to inhibit its kinase activity, stabilize β-catenin, and activate Wnt signaling, thereby upregulating repair-associated genes and mitigating chronic inflammation (196, 197). Inhibiting GSK3β effectively lowers TLR-driven TNF-α, IFN-γ, and IL-12 levels and improves the excessive-inflammation–associated mortality observed in Cul4b-deficient mice, suggesting that targeting GSK3β can restrain TLR-related hyperinflammation, restore local immune homeostasis, and promote tissue regeneration and healing (193, 198).

In addition, the TLR signaling adaptor BCAP (B-cell adaptor for PI3K) is critical for limiting overactivation in chronic wound inflammation. Through its YXXM motif, BCAP recruits the p85 subunit of PI3K to activate the PI3K/Akt pathway, indirectly suppressing GSK3β and FOXO1 activity and maintaining immune balance (199). BCAP deficiency reduces PI3K/Akt activity and anti-apoptotic signaling, resulting in persistent activation of inflammatory cells and impaired efferocytosis; increased exposure of self-antigens then drives excessive production of TNF-α, IL-1β, and IL-6, aggravating immune disequilibrium, prolonging the inflammatory phase, and suppressing repair (200–202). Conversely, enhancing BCAP activity may help re-establish local immune homeostasis and a balanced inflammatory milieu, thereby improving chronic wound healing. Notably, because PI3K/Akt signaling can indirectly enhance NF-κB activity, potential adverse effects should be carefully weighed when designing targeted interventions (203, 204).

Aberrant activation of macrophages and T cells is a central mechanism of healing impairment. Persistently activated M1 macrophages release large amounts of pro-inflammatory cytokines and delay the transition to reparative M2 phenotypes; in parallel, abnormal expansion and cytokine secretion by T cells—particularly Th1 and Th17 subsets—amplify inflammation and disrupt fibroblast function and angiogenesis (200, 205). Modulating TLR signaling to recalibrate macrophage and T-cell activation can both attenuate inflammation and restore the function of pro-repair immune populations, thereby accelerating healing in chronic wounds (206).

4.4 Targeted inhibition of NLRP3 inflammasome

4.4.1 Targeting NLRP3 mechanisms and promoting chronic wound healing

The IL-1β, IL-6, and IL-23 produced by the NLRP3 inflammasome are key factors in the differentiation of Th17 cells. Initial activation mediated by TLRs creates the necessary inflammatory microenvironment for Th17 differentiation, with IL-1β further enhancing Th17 generation by upregulating the transcription factor RORγt (207, 208). Activated Th17 cells secrete IL-17, which stimulates macrophages and fibroblasts to produce more IL-1β and IL-6, creating a pro-inflammatory positive feedback loop. Additionally, NLRP3 inflammasome activation can induce a shift in T_Reg metabolism from oxidative phosphorylation to glycolysis, impairing their immunosuppressive function. This imbalance between Th17 and T_Reg cells is a hallmark of chronic inflammatory tissues. The TLR-NLRP3 signaling axis forms a self-amplifying inflammatory circuit: TLR activation upregulates NLRP3 and pro-IL-1β expression (209). Subsequently, NLRP3 inflammasome activation leads to the maturation and secretion of IL-1β and IL-18; IL-1β, in turn, enhances TLR-NF-κB signaling, promoting M1 macrophage polarization and Th17 expansion, which releases more pro-inflammatory mediators like IL-6 and TNF-α (210–212). In this loop, M2 macrophages and T_Reg are unable to effectively exert their negative regulatory roles, causing inflammation to transition from an acute response to a persistent chronic state. For instance, in atherosclerosis, TLR4/NLRP3 signaling promotes foam cell formation and exacerbates vascular wall inflammation; in rheumatoid arthritis, the synergistic action of IL-1β and IL-17 amplifies synovial damage (210, 213).

In the delayed healing process of chronic wounds, a persistently activated inflammatory microenvironment is a significant factor hindering tissue repair. As a key regulatory node in the innate immune response, abnormal activation of the NLRP3 inflammasome exacerbates tissue damage and impedes healing. Studies have shown that MCC950, a selective NLRP3 inhibitor, can bind to the NACHT domain of NLRP3, preventing its conformational change and blocking ATPase activity. This significantly reduces the intensity of inflammation and decreases tissue destruction (214, 215). Meanwhile, TLRs, as upstream signaling molecules of the inflammasome, can promote the activation of NLRP3 inflammasomes by initiating the initial signaling, further amplifying the inflammatory response mediated by mature cytokines such as IL-1α, IL-1β, IL-18, and IL-33, thus forming a TLR4/NF-κB/NLRP3 positive feedback loop that delays wound repair (216, 217). In chronic wound tissues, abnormal activation of the NLRP3 inflammasome is often associated with gut microbiota dysbiosis and local immune disturbances, leading to the production of a large amount of type III cytokines and creating an inflammation-resistant environment. MCC950 (also known as CRID3) specifically inhibits the assembly and activation of the NLRP3 inflammasome, significantly reducing the secretion and release of IL-1β and IL-18, weakening chronic inflammation and providing a more favorable immune environment for wound repair (218–220). Notably, MCC950 does not affect the function of other inflammasomes, such as AIM2 and NLRC4, demonstrating its high specificity and clinical application potential. Moreover, immune imbalance in chronic wounds is not only reflected in abnormal inflammasome activation but also involves dysfunction of macrophages and T cells. Over-activated M1 macrophages continue to secrete pro-inflammatory factors, hindering the tissue repair function mediated by M2 macrophages, while excessive activation of effector T cells further amplifies the inflammatory response, resulting in wounds remaining in a prolonged inflammatory state (221). By inhibiting the NLRP3 inflammasome and its associated pathways, the abnormal activity of M1 macrophages and pro-inflammatory T cells can be indirectly reduced, promoting the differentiation of M2 macrophages and the restoration of T_Reg. This reprogramming of immune cell subsets not only helps alleviate inflammation but also accelerates neovascularization and matrix deposition, thus effectively promoting chronic wound healing (215, 222). In summary, targeting the persistently activated NLRP3 inflammasome can not only relieve excessive inflammation in chronic wounds but also reshape the immune balance of macrophages and T cells, offering a novel therapeutic strategy to enhance tissue repair and regenerate hard-to-heal wounds (221).

4.4.2 Off-target effects of NLRP3 inhibitors

MCC950 is one of the most widely used NLRP3 inflammasome inhibitors, primarily inhibiting inflammasome assembly by blocking the ATPase activity of NLRP3. However, several studies have shown significant off-target effects of MCC950. First, at high concentrations, MCC950 can also inhibit the activation of other inflammasomes, such as NLRC4 and AIM2, suggesting that its action may involve shared regulatory elements, such as NEK7 or mitochondrial ROS (222, 223). Second, MCC950 can interfere with potassium efflux and cell membrane polarization, thus affecting various Ca²⁺-dependent signaling pathways, which is related to its hydrophobic scaffold-mediated membrane binding capacity (224). Moreover, MCC950 has been shown to modulate glycolysis and fatty acid oxidation, which, while helping to reduce NLRP3 activation, may also alter macrophage polarization and T cell metabolic reprogramming, both energy-dependent processes (225, 226). Therefore, the off-target effects of MCC950 are not confined to a single molecular deviation but represent multi-layered interference in inflammatory signaling, membrane electrophysiology, and metabolic reprogramming.

In addition to MCC950, several other NLRP3 inhibitors developed in recent years, such as OLT1177, CY-09, and Oridonin, also exhibit varying degrees of off-target non-specific effects. OLT1177 (dapansutrile) has shown good safety in animal experiments and early clinical trials, but some of its anti-inflammatory effects are related to the inhibition of the IKKβ/NF-κB pathway, not solely dependent on NLRP3 blockade (227). CY-09 competes with ATP by binding to the NACHT domain of NLRP3, but in vitro studies have shown that it also inhibits AMPK phosphorylation, suggesting non-specific interference with energy sensing pathways (228). The natural product Oridonin, due to its ability to covalently bind to multiple thiol-containing proteins, not only inhibits NLRP3 but also broadly affects oxidative stress-related signaling and increases cytotoxicity (229). These findings indicate that, even with structural modifications to enhance targeting, small molecules, especially highly reactive natural products, still face significant off-target risks.

The off-target effects of NLRP3 inhibitors present dual impacts in both basic research and clinical translation. On one hand, non-specific inhibition of NF-κB, ROS generation, or metabolic reprogramming may synergistically reduce inflammation, creating an “apparent efficacy” that could be perceived as more effective than actual NLRP3-specific inhibition, thus distorting the accurate interpretation of the mechanism of action (230, 231). On the other hand, such effects may weaken the host’s anti-infection immunity, affect liver drug-metabolizing enzyme activity, induce mitochondrial dysfunction, and even compromise the gut barrier. For patients with chronic diseases requiring long-term medication, prolonged exposure to non-selective inhibitors could potentially induce immune tolerance and metabolic disorders, increasing the risk of adverse effects (226, 232). Therefore, the off-target nature of NLRP3 inhibitors has become a key bottleneck in drug optimization and clinical translation. Future research should combine structural optimization with multi-omics strategies, such as chemical proteomics and single-cell transcriptomics, to systematically map the global effect profile of these inhibitors. Additionally, structural biology and molecular dynamics simulations can be employed to accurately identify critical binding sites and potential non-specific interaction regions. Based on these insights, the development of inducible or tissue-specific NLRP3 inhibition strategies, such as prodrug design, nanoparticle delivery systems, and gene editing regulation, is expected to reduce off-target risks while enabling more precise and safer immune interventions.

4.5 Inflammatory microenvironment promotes tissue repair and chronic wound healing

4.5.1 Interactions between macrophages and T cells in the inflammatory microenvironment

At the level of immune regulation, the dynamic transition of macrophage phenotypes is a critical pivot in the progression of a wound from the inflammatory phase to the repair phase. Different T cell subsets finely shape macrophage fate through cytokine feedback loops. IFN-γ, secreted by Th1 cells and CD8⁺ T cells, maintains the inflammatory phenotype of macrophages, prolonging the local pathogen clearance and tissue degradation process in the lesion (233). In contrast, IL-4 and IL-13 produced by Th2 cells drive macrophages to polarize towards a repair-promoting phenotype, facilitating matrix remodeling and angiogenesis (234). IL-17 secreted by Th17 cells enhances neutrophil recruitment and amplifies the inflammatory response, thereby delaying the resolution of inflammation (234). T_Reg through the secretion of IL-10, TGF-β, and Amphiregulin, suppress excessive inflammation and directly or indirectly promote tissue repair and regeneration, effectively “braking” macrophage activation (235).

Building on this, the immune checkpoint axis PD-1 (on T cells)–PD-L1 (on macrophages, fibroblasts, neutrophils, and other cells) further limits the function of effector T cells and reversely remodels macrophage transcriptional and metabolic programs (236). The functional effects of this axis vary depending on disease type and the stage of wound healing. In chronic inflammatory environments, overactivation of the PD-1/PD-L1 axis may exacerbate immune suppression and stabilize the inflammatory phenotype (237). In contrast, in the early stages of acute injury, moderate enhancement of this axis helps prevent further tissue damage (238). Therefore, interventions targeting the PD-1/PD-L1 pathway must be precisely aligned with the disease progression and tissue microenvironment. Additionally, macrophages present antigens through MHC-II and co-stimulatory molecules, directly shaping the differentiation profile of CD4⁺ T cells. IFN-γ-induced chemokines such as CXCL9 and CXCL10 continuously recruit effector T cells in chronic wounds, resulting in an “inflammatory residence” state. Single-cell sequencing and spatial omics data indicate that these signaling axes differ significantly between healing wounds and chronic non-healing wounds (239, 240).

Beyond cytokines and receptor signaling, the metabolic microenvironment is another crucial dimension in regulating macrophage–T cell interactions. Hypoxia, high lactate levels, and reprogrammed glucose flux in damaged tissues simultaneously alter the metabolic preferences of both macrophages and T cells. Persistent glycolysis and lactate accumulation not only lock macrophages into an inflammatory phenotype but also impact T cell differentiation and effector function, ultimately creating a “metabolism–immune” coupled pathological loop (241, 242). Breaking this vicious cycle and restoring the spatiotemporal dynamics of macrophage phenotypes could become a key entry point for promoting the transition of chronic inflammation to effective repair in wound healing.

4.5.2 Targeting macrophages and T cells in the inflammatory microenvironment

In delayed or non-healing chronic wounds, neutrophils are among the first immune cells to accumulate at the site of injury, where they generate high levels of ROS via respiratory burst. Excessive ROS not only causes direct tissue damage but also promotes monocyte polarization toward pro-inflammatory M1 macrophages, aberrant activation of effector T cells, and full activation of the NLRP3 inflammasome (243, 244). Together, these events maintain prolonged inflammation in chronic wounds and inhibit tissue repair. Nuclear factor erythroid 2–related factor 2 (Nrf2) is the central transcription factor regulating antioxidant responses. Under oxidative stress, Nrf2 dissociates from its cytoplasmic inhibitor Keap1 and translocates into the nucleus, where it binds antioxidant response elements (AREs) to induce genes such as HO-1 and NQO1. This reduces ROS levels and attenuates inflammation. Studies have shown that dimethyl fumarate activates Nrf2 by covalently modifying Keap1 cysteine residues, while curcumin stabilizes Nrf2 by blocking its ubiquitin-mediated degradation, thereby enhancing both antioxidant and anti-inflammatory effects (245). Moreover, itaconate and its derivative 4-octyl itaconate (4-OI) not only release Nrf2 from Keap1 inhibition but also directly modify NLRP3, reducing excessive inflammasome activation and markedly lowering inflammatory responses in preclinical models (246). These findings suggest that targeting the Nrf2 pathway holds therapeutic potential for chronic wound healing.

From an immunoregulatory perspective, macrophage functional reprogramming is essential for repair. In chronic wounds, excessive M1 activation perpetuates inflammation, whereas M2 macrophages produce pro-repair mediators that promote angiogenesis, collagen deposition, and tissue remodeling (247–249). Thus, inhibiting ROS and NLRP3 inflammasome activity to drive M1-to-M2 repolarization may restore immune balance and accelerate healing. Likewise, effector T cells are often overactivated in chronic wounds, releasing large amounts of inflammatory cytokines (250). Correcting T-cell hyperactivation while enhancing T_Reg -mediated immunosuppression can improve the local immune environment and support tissue repair (251, 252).

In addition, extracellular ATP drives membrane depolarization and potassium efflux through P2X7 receptor (P2X7R) activation, a key trigger of NLRP3 inflammasome assembly. Selective P2X7R antagonists such as AZD9056 have shown potential in clinical trials for inflammatory diseases, although with variable efficacy; these results suggest that blocking the ATP–P2X7R axis could represent a viable approach in chronic wound therapy (253). Similarly, NADPH oxidase inhibitors, by reducing ROS production, also demonstrate promise in mitigating chronic inflammation and enhancing repair (254). In summary, targeting ROS and ATP mediated NLRP3 inflammasome activation, together with modulation of macrophage and T cell imbalance, not only alleviates persistent inflammation but also facilitates the transition from the inflammatory to the reparative phase, thereby offering new therapeutic opportunities for refractory wounds.

4.6 Contextual utilization of IL-17/TGF-β

4.6.1 Mechanism of contextual utilization of IL-17/TGF-β

IL-17 is an important pro-inflammatory cytokine produced by Th17 cells, γδT cells, and neutrophils. During the early stages of acute wound healing, IL-17 plays a crucial role by recruiting neutrophils, enhancing the expression of antimicrobial peptides, and stimulating fibroblasts to secrete IL-6 and CXCL8, all of which contribute to pathogen clearance and tissue debris removal (255, 256). However, in chronic wounds, the sustained high expression of IL-17 leads to excessive infiltration of inflammatory cells, causing tissue damage and a vicious cycle of oxidative stress.

To address this issue, a key strategy lies in the “temporal regulation” of IL-17. In the early phase of wound healing, moderate activation of IL-17 signaling can enhance immune clearance efficiency. However, in the later stages of wound healing, downregulating IL-17 signaling using TGF-β or exogenous IL-17 receptor antagonists can help resolve inflammation and promote the transition of macrophages from the M1 to the M2 phenotype (257, 258). This “stage-specific utilization—reversal inhibition” strategy demonstrates a contextual approach to managing IL-17, maintaining its immune advantages in the early phase while avoiding its pro-inflammatory side effects in the chronic stage.

TGF-β plays a central role in tissue regeneration and the reversal of inflammation. Through SMAD2/3-mediated transcriptional regulation, TGF-β promotes fibroblast migration and collagen deposition while inhibiting NF-κB signaling and promoting the generation of Foxp3⁺ T_reg, driving the conversion of inflammation to repair (259, 260). However, in chronic wound models, oxidative stress and a persistent IL-17/TNF-α environment often suppress the action of TGF-β signaling (261). Notably, there exists a feedback relationship between TGF-β and IL-17: TGF-β suppresses the expression of RORγt, inhibiting the differentiation of Th17 cells and thus forming a negative regulatory loop (262).

In the immune system, the interaction between IL-17 and TGF-β is not a simple antagonistic relationship, but rather a bidirectional regulatory mechanism based on the concentration of these cytokines, cell sources, and the timing of signals. Early in inflammation, low concentrations of TGF-β, along with IL-6 and IL-23, coexist to promote the differentiation of Th0 cells to Th17 cells, thereby producing IL-17 to respond to infection (95). Subsequently, sustained TGF-β signaling promotes the generation of T_Reg and inhibits Th17 cells, forming a self-limiting inflammatory loop (263, 264). In chronic wounds, restoring the dominant TGF-β signaling pathway becomes crucial for utilizing the endogenous regulatory mechanisms. This approach helps induce M2 macrophages to upregulate IL-10 and Arg-1, clearing residual inflammatory cells and promoting angiogenesis. The transition from IL-17-dominant to TGF-β-dominant signaling forms the molecular basis for inflammation resolution and tissue repair.

4.6.2 Targeting IL-17/TGF-β

Among the pathological drivers of delayed or non-healing chronic wounds, sustained hyperactivation of the IL-23/IL-17 axis is recognized as a major contributor to maintaining the pro-inflammatory microenvironment (264, 265). Within chronic wound tissues, IL-17F plays a pivotal role in promoting neutrophil recruitment and activation, thereby aggravating tissue injury and delaying repair (266, 267). Compared with TNF-α blockade, targeting IL-17A and IL-23 offers higher specificity and efficacy in controlling inflammation (268, 269). Preclinical studies have demonstrated that dual neutralization of IL-17A and IL-17F with antibodies such as bimekizumab significantly reduces cytokine release and neutrophil chemotaxis, thereby attenuating persistent local inflammation and promoting repair (270, 271). Another monoclonal antibody, ustekinumab, simultaneously blocks IL-12 and IL-23 signaling, effectively suppressing Th1 and Th17 overactivation and showing potential to reduce tissue injury and improve reparative conditions in chronic inflammation models (272–274).

Moreover, inflammasome activation in chronic wounds elevates systemic IL-1β and IL-18 levels, which further stimulate IL-23, IL-17A, and IL-22 expression, intensifying local immune imbalance (275, 276). At the same time, cyclooxygenases (COX-1/COX-2), key enzymes in inflammatory signaling, are aberrantly activated in wound tissues, enhancing prostaglandin synthesis and sustaining Th17-driven IL-17A secretion (277, 278). Selective COX-2 inhibitors such as celecoxib partially mitigate chronic inflammation, while novel agents such as β-D-mannuronic acid (M2000) directly bind COX-2, block its catalytic activity, and inhibit NF-κB signaling, thereby improving the local repair microenvironment (279–281). It is important to note that impaired macrophage phenotype switching and T-cell dysfunction also contribute to chronic wound persistence. Under normal conditions, M1 macrophages clear pathogens and necrotic tissue early in healing, before transitioning into M2 phenotypes that promote angiogenesis and matrix remodeling (282, 283). In chronic wounds, however, persistent pro-inflammatory signaling traps macrophages in the M1 state, leading to continuous secretion of IL-1β and TNF-α and perpetuating a deleterious feedback loop. Targeting macrophage polarization to suppress aberrant M1 activation and restore M2 functions could break this inflammatory deadlock and accelerate repair. Similarly, imbalanced CD4⁺ T-cell subsets—particularly hyperactive Th17 cells and insufficient T_Reg activity—play a key role in impaired healing. Restoring the Th17/T_Reg balance by limiting Th17 expansion and enhancing T_Reg-mediated immunoregulation represents a promising strategy for chronic wound therapy (Figure 2).

Figure 2

Figure 2. Aberrant APC activation drives delayed or non-healing skin tissue. (a) Resting state Tregs express high levels of CTLA-4, which binds to low levels of B7 molecules (CD80/CD86) on APCs. This binding competitively inhibits the CD28-mediated costimulatory signal, thereby limiting the activation of Th cells and CTLs, and maintaining an immune homeostasis conducive to repair. The PD-1 receptor on T cells binds to PD-L1/PD-L2 on APCs, transmitting an inhibitory signal that further suppresses the functions of both T cells and APCs. Additionally, Tregs secrete IL-10 and TGF-β, while MDSCs release ARG1 and iNOS, which directly inhibit the activity of effector T cells. The ectonucleotidases CD39 and CD73 convert ATP/ADP into AMP, which is further converted into adenosine. Adenosine acts on the A2A receptor on T cells, further limiting their activation. In summary, these layered “brake” mechanisms reduce immune-mediated damage to epithelial cells and fibroblasts at the wound edge, preserve the integrity of the extracellular matrix and microvascular network, and support wound healing as planned, rather than allowing the wound to progress to a delayed or non-healing state. (b) Activated state. In the “activated state,” abnormally degraded proteins and immune complexes formed by antibodies are recognized through their Fc regions, leading to their uptake, processing, and presentation by APCs, resulting in APC hyperactivation. The upregulation of costimulatory molecules (such as CD40, CD80/CD86, and ICOS) occurs, along with increased secretion of IFN-γ, IL-12, IL-2, and IL-23, which enhances antigen presentation and drives the differentiation of MDSCs and Th0 (CD4⁺ T cells) into M1/Th1/Th2/Th17 subsets. This simultaneously amplifies both CTL-mediated cellular immunity and B cell-mediated humoral immunity. High CD40L expression on Th2 cells further facilitates the full activation of B cells, while IL-2 promotes the proliferation and differentiation of CD8⁺ T cells into effector CTLs. At the same time, the downregulation of negative checkpoint molecules (such as CTLA-4 and PD-1) weakens inhibitory signals, causing Th1, Th2, Th17 cells, and CTLs to become hyperactive and dysregulated. Effector CTLs are subsequently directed to damaged tissues or wounds, where they seek and attack cells bearing self-antigens or damage-associated epitopes. This results in the suppression or killing of epithelial cells and fibroblasts, perpetuating the exposure of self-antigens and the failure to clear them. This leads to a vicious cycle of immune activation and tissue destruction, ultimately resulting in delayed or non-healing of the wound.

Therefore, targeted inhibition of the IL-23/IL-17 axis and related inflammatory pathways, in combination with modulation of macrophage and T cell dysregulation, holds the potential to markedly improve the chronic wound inflammatory microenvironment and facilitate tissue repair. Collectively, these findings highlight the future direction of precision immunomodulation as a cornerstone in chronic wound management.

5 Future directions and challenges

5.1 Research gaps in the current field

Wound healing is a complex biological process involving multiple layers, such as inflammation, cell migration, angiogenesis, and tissue remodeling. Over the past decades, significant progress has been made in understanding the cellular and molecular mechanisms of healing phases. However, there remains a substantial gap in translating these basic research findings into effective clinical interventions, especially for pathological wounds such as chronic wounds, age-related skin lesions, and diabetes-related ulcers. The limited effectiveness of traditional treatments for these conditions indicates that current understanding of the dynamic changes in the wound microenvironment, immune regulatory networks, and tissue regeneration mechanisms is still insufficient (284). First, incomplete understanding of inflammation and immune response regulation remains a major challenge. The first phase of wound healing—the inflammatory response—plays a central role in activating immune defense mechanisms and initiating the repair response (285). However, current research tends to focus on the relative expression of pro-inflammatory and anti-inflammatory cytokines, lacking a systematic exploration of the “resolution process” of inflammation. For example, the mechanisms of immune cell conversion are insufficiently explored. The phenotypic transitions of macrophages, dendritic cells, and neutrophils at different stages of wound healing are still unclear, and how their plasticity is influenced by local metabolism, mechanical stress, and extracellular vesicle signaling remains to be investigated in greater depth. Furthermore, there is a lack of research on the intersection between immune and metabolic regulation. Recent evidence suggests that metabolic reprogramming directly determines the functional orientation of immune cells (3), yet its role in chronic wound inflammation has not been systematically validated. Second, limitations in studying the microenvironment and ECM signaling hinder further progress. The success of wound healing depends on the coordination between the ECM and intercellular signaling. However, existing research often focuses on isolated signaling pathways (e.g., TGF-β/Smad or VEGF/VEGFR) (286, 287), with insufficient understanding of how multi-signal coupling and physical microenvironmental factors (such as tension, oxygen tension, and ion concentration gradients) work together. For example, there is a lack of integrated studies on the “dynamic microenvironment.” Most experiments are conducted using two-dimensional or static culture models, which fail to reflect the true impact of in vivo three-dimensional tension and temporal chemical gradients on cellular behavior. The precise description of ECM remodeling mechanisms is also lacking. The time sequence of matrix degradation and reconstruction, feedback signaling, and their interactions with immune cells have not yet formed a comprehensive theoretical framework.

5.2 Future directions and challenges

To address the core issues of sustained inflammation and immune imbalance in wound healing, future research should focus on the dynamic regulation of immune responses and the resolution of inflammation (288). By integrating single-cell transcriptomics, spatial omics, and metabolomics data, we aim to construct spatiotemporal immune maps that reveal the dynamic interactions of macrophages, dendritic cells, and T cells at different stages of healing (289, 290) This approach will provide a molecular foundation for identifying key nodes in inflammation resolution. Moreover, strategies should be developed to precisely intervene in the immune-metabolic coupling, such as using small molecule metabolic regulators or epigenetic modulators to achieve controlled conversion of immune cells from a “pro-inflammatory” to a “repair-promoting” state. The future focus should not solely be on suppressing inflammation, but rather on actively reshaping immune homeostasis, which aims to restore dynamic balance in the immune system without compromising host defense.

Given the complexity and spatiotemporal heterogeneity of the wound microenvironment, traditional two-dimensional models are insufficient for capturing the true biomechanical and signaling gradients. High-fidelity three-dimensional biological response models should be developed, integrating mechanobiology and computational simulations to systematically analyze the combined effects of mechanical stress, oxygen tension, and ion gradients on cellular behavior. In terms of technology, combining spatiotemporal single-cell omics with in vivo imaging techniques can enable real-time tracking of the ECM remodeling process, revealing the dynamic regulatory networks involved in matrix degradation and regeneration. The integration of machine learning algorithms to process and analyze these multi-dimensional datasets could help discover new “microenvironmental regulatory factors,” guiding the optimization of biomaterials and drug delivery systems. This could facilitate the shift from descriptive studies to predictive and interventional models.

In the later stages of healing, tissue reconstruction relies on the coordinated action of multiple cell types, including fibroblasts, keratinocytes, endothelial cells, and neurons. Future research should move beyond focusing on individual signaling axes and construct multicellular signaling interaction network models to explore the integrative mechanisms of the neuro-immune-vascular axis in regenerative repair. By employing multi-scale systems biology methods to model the spatial coupling of various signaling pathways, such as TGF-β, VEGF, Notch, and Wnt, we can identify critical regulatory nodes that control the quality of healing (291) This will lay the theoretical foundation for developing comprehensive therapeutic strategies that simultaneously regulate immune responses, angiogenesis, and ECM remodeling.

6 Conclusion

Chronic wounds and delayed or non-healing wounds remain significant clinical challenges, and there is currently a lack of drug strategies that can effectively block the sustained activation of the inflammatory response or improve long-term healing outcomes. Just as the intersection of immunology and pharmacology has driven cancer treatment into a new era of “immunopharmacology,” targeting immune imbalance strategies also hold the potential to revolutionize the treatment of chronic non-healing wounds (292, 293). By inducing and maintaining immune homeostasis, it may be possible to more effectively improve the local wound environment, accelerate tissue repair, and ultimately enhance patients’ quality of life and long-term prognosis (294).

Targeting and modulating the chronically activated inflammatory microenvironment to restore immune homeostasis represents an exciting direction for promoting wound healing (295). In chronic wounds, abnormal inflammatory responses driven by both genetic susceptibility and environmental factors often manifest as the persistent overactivation of macrophages and T cells (296). This immune cell dysfunction not only leads to the prolonged secretion of pro-inflammatory cytokines but also suppresses the normal functions of repair-related cells such as fibroblasts, keratinocytes, and endothelial cells, resulting in delayed wound healing (297). Therefore, reprogramming the activity of macrophages and T cells through epigenetic regulation, signaling pathway interventions, and specific inhibitors, to shift them from a “pro-inflammatory” state to a “repair-promoting” state, becomes a central breakthrough for chronic wound treatment.

Although significant progress has been made in understanding how immune cells remodel their function through signaling molecules, several key scientific questions remain to be addressed, including: (1) How do environmental factors in different individuals and populations synergistically influence immune cell activity, and how can we develop precision and personalized therapeutic strategies based on this. (2) How do dynamic changes in epigenetic markers, such as DNA methylation and histone modifications, in the chronic wound inflammatory microenvironment specifically affect gene transcription and cellular function, and how can epigenetic interventions reverse the inflammation-driven wound stagnation. (3) How can we precisely regulate the abnormal activation of macrophages and T cells without weakening normal immune defense.

Furthermore, understanding how upstream immune pathways, such as TCR signaling and cytokine receptors, shape immune cell functional programs may provide new targets for cell-based therapies (298). By precisely modulating these signals, it may be possible to shift the immune microenvironment from a continuously activated inflammatory state to a homeostatic repair state, offering a novel treatment model for chronic wounds (299, 300). These emerging therapeutic strategies not only have the potential to further improve patients’ quality of life but also provide more efficient and personalized solutions for complex immune-mediated non-healing wounds.

Author contributions

YD: Writing – original draft. YC: Writing – review & editing.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Acknowledgments

We would like to express our appreciation to everyone involved in drafting and preparing the manuscript.

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nüchel J, et al. Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab. (2021) 33:2398–2414.e9. doi: 10.1016/j.cmet.2021.10.004

PubMed Abstract | Crossref Full Text | Google Scholar

2. Whitaker R, Hernaez-Estrada B, Hernandez RM, Santos-Vizcaino E, and Spiller KL. Immunomodulatory biomaterials for tissue repair. Chem Rev. (2021) 121:11305–35. doi: 10.1021/acs.chemrev.0c00895

PubMed Abstract | Crossref Full Text | Google Scholar

3. Eming SA, Murray PJ, and Pearce EJ. Metabolic orchestration of the wound healing response. Cell Metab. (2021) 33:1726–43. doi: 10.1016/j.cmet.2021.07.017

PubMed Abstract | Crossref Full Text | Google Scholar

4. Yang P, Lu Y, Gou W, Qin Y, Zhang X, Li J, et al. Andrias davidianus derived glycosaminoglycans direct diabetic wound repair by reprogramming reparative macrophage glucolipid metabolism. Adv Mater. (2025) 37:e2417801. doi: 10.1002/adma.202417801

PubMed Abstract | Crossref Full Text | Google Scholar

5. Villarreal-Leal RA, Healey GD, and Corradetti B. Biomimetic immunomodulation strategies for effective tissue repair and restoration. Adv Drug Delivery Rev. (2021) 179:113913. doi: 10.1016/j.addr.2021.113913

PubMed Abstract | Crossref Full Text | Google Scholar

6. Wen Q, Mithieux SM, and Weiss AS. Elastin biomaterials in dermal repair. Trends Biotechnol. (2020) 38:280–91. doi: 10.1016/j.tibtech.2019.08.005

PubMed Abstract | Crossref Full Text | Google Scholar

7. du Halgouet A, Darbois A, Alkobtawi M, Mestdagh M, Alphonse A, Premel V, et al. Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing. Immunity. (2023) 56:78–92.e6. doi: 10.1016/j.immuni.2022.12.004

PubMed Abstract | Crossref Full Text | Google Scholar

8. Dekoninck S and Blanpain C. Stem cell dynamics, migration and plasticity during wound healing. Nat Cell Biol. (2019) 21:18–24. doi: 10.1038/s41556-018-0237-6

PubMed Abstract | Crossref Full Text | Google Scholar

9. Talbott HE, Mascharak S, Griffin M, Wan DC, and Longaker MT. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. (2022) 29:1161–80. doi: 10.1016/j.stem.2022.07.006

PubMed Abstract | Crossref Full Text | Google Scholar

10. Sarate RM, Hochstetter J, Valet M, Hallou A, Song Y, Bansaccal N, et al. Dynamic regulation of tissue fluidity controls skin repair during wound healing. Cell. (2024) 187:5298–5315.e19. doi: 10.1016/j.cell.2024.07.031

PubMed Abstract | Crossref Full Text | Google Scholar

11. Roefs MT, Sluijter JPG, and Vader P. Extracellular vesicle-associated proteins in tissue repair. Trends Cell Biol. (2020) 30:990–1013. doi: 10.1016/j.tcb.2020.09.009

PubMed Abstract | Crossref Full Text | Google Scholar

12. Khan F, Pang L, Dunterman M, Lesniak MS, Heimberger AB, and Chen P. Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy. J Clin Invest. (2023) 133:e163446. doi: 10.1172/JCI163446

PubMed Abstract | Crossref Full Text | Google Scholar

13. Yan L, Wang J, Cai X, Liou YC, Shen HM, Hao J, et al. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm. (2024) 5:e658. doi: 10.1002/mco2.658

PubMed Abstract | Crossref Full Text | Google Scholar

14. De Vlaminck K, Van Hove H, Kancheva D, Scheyltjens I, Pombo Antunes AR, Bastos J, et al. Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation. Immunity. (2022) 55:2085–2102.e9. doi: 10.1016/j.immuni.2022.09.005

PubMed Abstract | Crossref Full Text | Google Scholar

15. Chen R, Zhang H, Tang B, Luo Y, Yang Y, Zhong X, et al. Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. (2024) 9:130. doi: 10.1038/s41392-024-01840-1

PubMed Abstract | Crossref Full Text | Google Scholar

16. Luo M, Zhao F, Cheng H, Su M, and Wang Y. Macrophage polarization: an important role in inflammatory diseases. Front Immunol. (2024) 15:1352946. doi: 10.3389/fimmu.2024.1352946

PubMed Abstract | Crossref Full Text | Google Scholar

17. Pan Y, Yu Y, Wang X, and Zhang T. Tumor-associated macrophages in tumor immunity. Front Immunol. (2020) 11:583084. doi: 10.3389/fimmu.2020.583084

PubMed Abstract | Crossref Full Text | Google Scholar

18. Peña OA and Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. (2024) 25:599–616. doi: 10.1038/s41580-024-00715-1

PubMed Abstract | Crossref Full Text | Google Scholar

19. Park DJ, Duggan E, Ho K, Dorschner RA, Dobke M, Nolan JP, et al. Serpin-loaded extracellular vesicles promote tissue repair in a mouse model of impaired wound healing. J Nanobiotechnol. (2022) 20:474. doi: 10.1186/s12951-022-01656-7

PubMed Abstract | Crossref Full Text | Google Scholar

20. Meng Z, Zhou D, Gao Y, Zeng M, and Wang W. miRNA delivery for skin wound healing. Adv Drug Delivery Rev. (2018) 129:308–18. doi: 10.1016/j.addr.2017.12.011

PubMed Abstract | Crossref Full Text | Google Scholar

21. Mehrotra P, Maschalidi S, Boeckaerts L, Maueröder C, Tixeira R, Pinney J, et al. Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair. Nature. (2024) 631:207–15. doi: 10.1038/s41586-024-07585-9

PubMed Abstract | Crossref Full Text | Google Scholar

22. Mao K, Yue M, Ma H, Li Z, and Liu Y. Electro- and magneto-active biomaterials for diabetic tissue repair: advantages and applications. Adv Mater. (2025) 37:e2501817. doi: 10.1002/adma.202501817

PubMed Abstract | Crossref Full Text | Google Scholar

23. Lou P, Liu S, Wang Y, Lv K, Zhou X, Li L, et al. Neonatal-tissue-derived extracellular vesicle therapy (NEXT): A potent strategy for precision regenerative medicine. Adv Mater. (2023) 35:e2300602. doi: 10.1002/adma.202300602

PubMed Abstract | Crossref Full Text | Google Scholar

24. Liu S, Shi L, Luo H, Chen K, Song M, Wu Y, et al. Processed microalgae: green gold for tissue regeneration and repair. Theranostics. (2024) 14:5235–61. doi: 10.7150/thno.99181

PubMed Abstract | Crossref Full Text | Google Scholar

25. Xiao Q, Li X, Li Y, Wu Z, Xu C, Chen Z, et al. Biological drug and drug delivery-mediated immunotherapy. Acta Pharm Sin B. (2021) 11:941–60. doi: 10.1016/j.apsb.2020.12.018

PubMed Abstract | Crossref Full Text | Google Scholar

26. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. (2011) 29:621–63. doi: 10.1146/annurev-immunol-031210-101400

PubMed Abstract | Crossref Full Text | Google Scholar

27. Li D, Liu Z, Zhang L, Bian X, Wu J, Li L, et al. The lncRNA SNHG26 drives the inflammatory-to-proliferative state transition of keratinocyte progenitor cells during wound healing. Nat Commun. (2024) 15:8637. doi: 10.1038/s41467-024-52783-8

PubMed Abstract | Crossref Full Text | Google Scholar

28. Keane TJ, Horejs CM, and Stevens MM. Scarring vs. functional healing: Matrix-based strategies to regulate tissue repair. Adv Drug Delivery Rev. (2018) 129:407–19. doi: 10.1016/j.addr.2018.02.002

PubMed Abstract | Crossref Full Text | Google Scholar

29. Kaplani K, Koutsi S, Armenis V, Skondra FG, Karantzelis N, Champeris Tsaniras S, et al. Wound healing related agents: Ongoing research and perspectives. Adv Drug Delivery Rev. (2018) 129:242–53. doi: 10.1016/j.addr.2018.02.007

PubMed Abstract | Crossref Full Text | Google Scholar

30. Hu KH, Kuhn NF, Courau T, Tsui J, Samad B, Ha P, et al. Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer. Cell Stem Cell. (2023) 30:885–903.e10. doi: 10.1016/j.stem.2023.05.001

PubMed Abstract | Crossref Full Text | Google Scholar

31. Guo Y, Ding S, Shang C, Zhang C, Li M, Zhang Q, et al. Multifunctional ptCuTe nanosheets with strong ROS scavenging and ROS-independent antibacterial properties promote diabetic wound healing. Adv Mater. (2024) 36:e2306292. doi: 10.1002/adma.202306292

PubMed Abstract | Crossref Full Text | Google Scholar

32. Guan T, Li J, Chen C, and Liu Y. Self-assembling peptide-based hydrogels for wound tissue repair. Adv Sci (Weinh). (2022) 9:e2104165. doi: 10.1002/advs.202104165

PubMed Abstract | Crossref Full Text | Google Scholar

33. Tang L, Cai S, Lu X, Wu D, Zhang Y, Li X, et al. Platelet-derived growth factor nanocapsules with tunable controlled release for chronic wound healing. Small. (2024) 20:e2310743. doi: 10.1002/smll.202310743

PubMed Abstract | Crossref Full Text | Google Scholar

34. Sun W, Dion E, Laredo F, Okonak A, Sepeda JA, Haykal E, et al. In vivo programming of adult pericytes aids axon regeneration by providing cellular bridges for SCI repair. Mol Ther. (2025) 33:3968–93. doi: 10.1016/j.ymthe.2025.04.020

PubMed Abstract | Crossref Full Text | Google Scholar

35. Shen T, Dai K, Zhang S, Wang J, and Liu C. Injured bone-triggered osteokines secretion promotes diabetic wound healing. Bone Res. (2025) 13:83. doi: 10.1038/s41413-025-00454-9

PubMed Abstract | Crossref Full Text | Google Scholar

36. Hassanshahi A, Moradzad M, Ghalamkari S, Fadaei M, Cowin AJ, and Hassanshahi M. Macrophage-mediated inflammation in skin wound healing. Cells. (2022) 11:2953. doi: 10.3390/cells11192953

PubMed Abstract | Crossref Full Text | Google Scholar

37. Deng H, Wang F, Zhou Y, Lei H, Zhou H, Chen S, et al. Biosynthesis of a dual growth factors (GFs) functionalized silk sericin hydrogel to promote chronic wound healing in diabetic mice. Bioact Mater. (2025) 52:511–28. doi: 10.1016/j.bioactmat.2025.06.017

PubMed Abstract | Crossref Full Text | Google Scholar

38. He F, Xu P, Zhu Z, Zhang Y, Cai C, Zhang Y, et al. Inflammation-responsive hydrogel accelerates diabetic wound healing through immunoregulation and enhanced angiogenesis. Adv Healthcare Mater. (2025) 14:e2400150. doi: 10.1002/adhm.202400150

PubMed Abstract | Crossref Full Text | Google Scholar

39. Huang J, Heng S, Zhang W, Liu Y, Xia T, Ji C, et al. Dermal extracellular matrix molecules in skin development, homeostasis, wound regeneration and diseases. Semin Cell Dev Biol. (2022) 128:137–44. doi: 10.1016/j.semcdb.2022.02.027

PubMed Abstract | Crossref Full Text | Google Scholar

40. Lin P, Zhang G, and Li H. The role of extracellular matrix in wound healing. Dermatol Surg. (2023) 49:S41–s48. doi: 10.1097/DSS.0000000000003779

PubMed Abstract | Crossref Full Text | Google Scholar

41. Darby IA, Zakuan N, Billet F, and Desmoulière A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell Mol Life Sci: CMLS. (2016) 73:1145–57. doi: 10.1007/s00018-015-2110-0

PubMed Abstract | Crossref Full Text | Google Scholar

42. Lee JH and Massagué J. TGF-β in developmental and fibrogenic EMTs. Semin Cancer Biol. (2022) 86:136–45. doi: 10.1016/j.semcancer.2022.09.004

PubMed Abstract | Crossref Full Text | Google Scholar

43. Fan L, Jia X, Dong F, Yang S, Li W, Zhao R, et al. Ginseng-derived nanoparticles accelerate diabetic wound healing by modulating macrophage polarization and restoring endothelial cell function. Mater Today Bio. (2025) 34:102143. doi: 10.1016/j.mtbio.2025.102143

PubMed Abstract | Crossref Full Text | Google Scholar

44. Bonnici L, Suleiman S, Schembri-Wismayer P, and Cassar A. Targeting signalling pathways in chronic wound healing. Int J Mol Sci. (2023) 25:50. doi: 10.3390/ijms25010050

PubMed Abstract | Crossref Full Text | Google Scholar

45. Chu Z, Huang Q, Ma K, Liu X, Zhang W, Cui S, et al. Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles. Bioact Mater. (2023) 27:257–70. doi: 10.1016/j.bioactmat.2023.04.007

PubMed Abstract | Crossref Full Text | Google Scholar

46. Irma J, Kartasasmita AS, Kartiwa A, Irfani I, Rizki SA, and Onasis S. From growth factors to structure: PDGF and TGF-β in granulation tissue formation. A Literat Rev J Cell Mol Med. (2025) 29:e70374. doi: 10.1111/jcmm.70374

PubMed Abstract | Crossref Full Text | Google Scholar

47. Caley MP, Martins VL, and O’Toole EA. Metalloproteinases and wound healing. Adv Wound Care. (2015) 4:225–34. doi: 10.1089/wound.2014.0581

PubMed Abstract | Crossref Full Text | Google Scholar

48. Chi J, Zhang X, Chen C, Shao C, Zhao Y, and Wang Y. Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing. Bioact Mater. (2020) 5:253–9. doi: 10.1016/j.bioactmat.2020.02.004

PubMed Abstract | Crossref Full Text | Google Scholar

49. Zindel J and Kubes P. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation. Annu Rev Pathol. (2020) 15:493–518. doi: 10.1146/annurev-pathmechdis-012419-032847

PubMed Abstract | Crossref Full Text | Google Scholar

50. Seok JK, Kang HC, Cho YY, Lee HS, and Lee JY. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch Pharm Res. (2021) 44:16–35. doi: 10.1007/s12272-021-01307-9

PubMed Abstract | Crossref Full Text | Google Scholar

51. Xiao P, Cai X, Zhang Z, Guo K, Ke Y, Hu Z, et al. Butyrate prevents the pathogenic anemia-inflammation circuit by facilitating macrophage iron export. Adv Sci (Weinh). (2024) 11:e2306571. doi: 10.1002/advs.202306571

PubMed Abstract | Crossref Full Text | Google Scholar

52. Sorokin AV and Mehta NN. The relationship between TNF-alpha driven inflammation, lipids, and endothelial function in rheumatoid arthritis: a complex puzzle continues. Cardiovasc Res. (2022) 118:10–2. doi: 10.1093/cvr/cvab190

PubMed Abstract | Crossref Full Text | Google Scholar

53. Rolski F, Tkacz K, Węglarczyk K, Kwiatkowski G, Pelczar P, Jaźwa-Kusior A, et al. TNF-α protects from exacerbated myocarditis and cardiac death by suppressing expansion of activated heart-reactive CD4+ T cells. Cardiovasc Res. (2024) 120:82–94. doi: 10.1093/cvr/cvad158

PubMed Abstract | Crossref Full Text | Google Scholar

54. Hong YK, Chang YH, Lin YC, Chen B, Guevara BEK, and Hsu CK. Inflammation in wound healing and pathological scarring. Adv Wound Care. (2023) 12:288–300. doi: 10.1089/wound.2021.0161

PubMed Abstract | Crossref Full Text | Google Scholar

55. Zhou H, Zhang Q, Huang W, Zhou S, Wang Y, Zeng X, et al. NLRP3 inflammasome mediates silica-induced lung epithelial injury and aberrant regeneration in lung stem/progenitor cell-derived organotypic models. Int J Biol Sci. (2023) 19:1875–93. doi: 10.7150/ijbs.80605

PubMed Abstract | Crossref Full Text | Google Scholar

56. Pourcet B and Duez H. Circadian control of inflammasome pathways: implications for circadian medicine. Front Immunol. (2020) 11:1630. doi: 10.3389/fimmu.2020.01630

PubMed Abstract | Crossref Full Text | Google Scholar

57. Ropert C. How toll-like receptors reveal monocyte plasticity: the cutting edge of antiinflammatory therapy. Cell Mol Life Sci. (2019) 76:745–55. doi: 10.1007/s00018-018-2959-9

PubMed Abstract | Crossref Full Text | Google Scholar

58. Pellegrini L, Foglio E, Pontemezzo E, Germani A, Russo MA, and Limana F. HMGB1 and repair: focus on the heart. Pharmacol Ther. (2019) 196:160–82. doi: 10.1016/j.pharmthera.2018.12.005

PubMed Abstract | Crossref Full Text | Google Scholar

59. Ortiz Wilczyñski JM, Mena HA, Ledesma MM, Olexen CM, Podaza E, Schattner M, et al. The synthetic phospholipid C8-C1P determines pro-angiogenic and pro-reparative features in human macrophages restraining the proinflammatory M1-like phenotype. Front Immunol. (2023) 14:1162671. doi: 10.3389/fimmu.2023.1162671

PubMed Abstract | Crossref Full Text | Google Scholar

60. Liu X, Zhou Z, Zeng WN, Zeng Q, and Zhang X. The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology. Front Cell Dev Biol. (2023) 11:1277686. doi: 10.3389/fcell.2023.1277686

PubMed Abstract | Crossref Full Text | Google Scholar

61. Zhao J, Zhang S, Gong Z, Mao W, Bao W, Li Q, et al. NLRP3: a key regulator of skin wound healing and macrophage-fibroblast interactions in mice. Cell Commun Signal. (2025) 23:55. doi: 10.1186/s12964-025-02063-9

PubMed Abstract | Crossref Full Text | Google Scholar

62. Sayan M and Mossman BT. The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Part Fibre Toxicol. (2016) 13:51. doi: 10.1186/s12989-016-0162-4

PubMed Abstract | Crossref Full Text | Google Scholar

63. Dwyer GK and Turnquist HR. Untangling local pro-inflammatory, reparative, and regulatory damage-associated molecular-patterns (DAMPs) pathways to improve transplant outcomes. Front Immunol. (2021) 12:611910. doi: 10.3389/fimmu.2021.611910

PubMed Abstract | Crossref Full Text | Google Scholar

64. Mohapatra B, Lavudi K, Kokkanti RR, and Patnaik S. Regulation of NLRP3/TRIM family signaling in gut inflammation and colorectal cancer. Biochim Biophys Acta Rev Cancer. (2025) 1880:189271. doi: 10.1016/j.bbcan.2025.189271

PubMed Abstract | Crossref Full Text | Google Scholar

65. Liu D, Zhong Z, and Karin M. NF-κB: A double-edged sword controlling inflammation. Biomedicines. (2022) 10:1250. doi: 10.3390/biomedicines10061250

PubMed Abstract | Crossref Full Text | Google Scholar

66. Leemans JC, Kors L, Anders HJ, and Florquin S. Pattern recognition receptors and the inflammasome in kidney disease. Nat Rev Nephrol. (2014) 10:398–414. doi: 10.1038/nrneph.2014.91

PubMed Abstract | Crossref Full Text | Google Scholar

67. Chi Y, Jiang H, Yin Y, Zhou X, Shao Y, Li Y, et al. Macrophage signaling pathways in health and disease: from bench to bedside applications. MedComm. (2025) 6:e70256. doi: 10.1002/mco2.70256

PubMed Abstract | Crossref Full Text | Google Scholar

68. Lv D, Cao X, Zhong L, Dong Y, Xu Z, Rong Y, et al. Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing. Cell Rep Med. (2023) 4:101129. doi: 10.1016/j.xcrm.2023.101129

PubMed Abstract | Crossref Full Text | Google Scholar

69. Sharma BR and Kanneganti TD. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol. (2021) 22:550–9. doi: 10.1038/s41590-021-00886-5

PubMed Abstract | Crossref Full Text | Google Scholar

70. Kong H, Zhao H, Chen T, Song Y, and Cui Y. Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy. Cell Death Dis. (2022) 13:336. doi: 10.1038/s41419-022-04786-w

PubMed Abstract | Crossref Full Text | Google Scholar

71. Higashikuni Y, Liu W, Numata G, Tanaka K, Fukuda D, Tanaka Y, et al. NLRP3 inflammasome activation through heart-brain interaction initiates cardiac inflammation and hypertrophy during pressure overload. Circulation. (2023) 147:338–55. doi: 10.1161/CIRCULATIONAHA.122.060860

PubMed Abstract | Crossref Full Text | Google Scholar

72. Mancino A, Schioppa T, Larghi P, Pasqualini F, Nebuloni M, Chen IH, et al. Divergent effects of hypoxia on dendritic cell functions. Blood. (2008) 112:3723–34. doi: 10.1182/blood-2008-02-142091

PubMed Abstract | Crossref Full Text | Google Scholar

73. Ioannidis M, Cerundolo V, and Salio M. The immune modulating properties of mucosal-associated invariant T cells. Front Immunol. (2020) 11:1556. doi: 10.3389/fimmu.2020.01556

PubMed Abstract | Crossref Full Text | Google Scholar

74. Zhao Y, Lee CK, Lin CH, Gassen RB, Xu X, Huang Z, et al. PD-L1:CD80 cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways. Immunity. (2019) 51:1059–1073.e9. doi: 10.1016/j.immuni.2019.11.003

PubMed Abstract | Crossref Full Text | Google Scholar

75. Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science. (2019) 364:558–66. doi: 10.1126/science.aav7062

PubMed Abstract | Crossref Full Text | Google Scholar

76. Patel R, Kim K, Shutinoski B, Wachholz K, Krishnan L, and Sad S. Culling of APCs by inflammatory cell death pathways restricts TIM3 and PD-1 expression and promotes the survival of primed CD8 T cells. Cell Death Differ. (2017) 24:1900–11. doi: 10.1038/cdd.2017.112

PubMed Abstract | Crossref Full Text | Google Scholar

77. Pagliano O, Morrison RM, Chauvin JM, Banerjee H, Davar D, Ding Q, et al. Tim-3 mediates T cell trogocytosis to limit antitumor immunity. J Clin Invest. (2022) 132:e152864. doi: 10.1172/JCI152864

PubMed Abstract | Crossref Full Text | Google Scholar

78. Davda J, Declerck P, Hu-Lieskovan S, Hickling TP, Jacobs IA, Chou J, et al. Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics. J Immunother Cancer. (2019) 7:105. doi: 10.1186/s40425-019-0586-0

PubMed Abstract | Crossref Full Text | Google Scholar

79. Bodhankar S, Chen Y, Vandenbark AA, Murphy SJ, and Offner H. PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1. J Neuroinflamm. (2013) 10:111. doi: 10.1186/1742-2094-10-111

PubMed Abstract | Crossref Full Text | Google Scholar

80. Tournadre A and Miossec P. Chemokines and dendritic cells in inflammatory myopathies. Ann Rheum Dis. (2009) 68:300–4. doi: 10.1136/ard.2008.095984

PubMed Abstract | Crossref Full Text | Google Scholar

81. Tan C, Wei L, Vistica BP, Shi G, Wawrousek EF, and Gery I. Phenotypes of Th lineages generated by the commonly used activation with anti-CD3/CD28 antibodies differ from those generated by the physiological activation with the specific antigen. Cell Mol Immunol. (2014) 11:305–13. doi: 10.1038/cmi.2014.8

PubMed Abstract | Crossref Full Text | Google Scholar

82. Li WH, Su JY, and Li YM. Rational design of T-cell- and B-cell-based therapeutic cancer vaccines. Acc Chem Res. (2022) 55:2660–71. doi: 10.1021/acs.accounts.2c00360

PubMed Abstract | Crossref Full Text | Google Scholar

83. Kannan AK, Sahu N, Mohanan S, Mohinta S, and August A. IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells. J Allergy Clin Immunol. (2013) 132:811–20.e1-5. doi: 10.1016/j.jaci.2013.04.033

PubMed Abstract | Crossref Full Text | Google Scholar

84. Hilligan KL, Tang SC, Hyde EJ, Roussel E, Mayer JU, Yang J, et al. Dermal IRF4+ dendritic cells and monocytes license CD4+ T helper cells to distinct cytokine profiles. Nat Commun. (2020) 11:5637. doi: 10.1038/s41467-020-19463-9

PubMed Abstract | Crossref Full Text | Google Scholar

85. Gutcher I and Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. (2007) 117:1119–27. doi: 10.1172/JCI31720

PubMed Abstract | Crossref Full Text | Google Scholar

86. Gommerman JL, Rojas OL, and Fritz JH. Re-thinking the functions of IgA(+) plasma cells. Gut Microbes. (2014) 5:652–62. doi: 10.4161/19490976.2014.969977

PubMed Abstract | Crossref Full Text | Google Scholar

87. Bosteels C, Neyt K, Vanheerswynghels M, van Helden MJ, Sichien D, Debeuf N, et al. Inflammatory Type 2 cDCs Acquire Features of cDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection. Immunity. (2020) 52:1039–1056.e9. doi: 10.1016/j.immuni.2020.04.005

PubMed Abstract | Crossref Full Text | Google Scholar

88. Mundt S, Mrdjen D, Utz SG, Greter M, Schreiner B, and Becher B. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci Immunol. (2019) 4:eaau8380. doi: 10.1126/sciimmunol.aau8380

PubMed Abstract | Crossref Full Text | Google Scholar

89. Kamal K, Richardsdotter-Andersson E, Dondalska A, Wahren-Herlenius M, and Spetz AL. A non-coding oligonucleotide recruits cutaneous CD11b(+) cells that inhibit thelper responses and promote tregs. Adv Sci (Weinh). (2024) 11:e2400260. doi: 10.1002/advs.202400260

PubMed Abstract | Crossref Full Text | Google Scholar

90. Jin C, Zhang Y, Li B, Gao T, Wang B, and Hua P. Robust anti-tumor immunity through the integration of targeted lipid nanoparticle-based mRNA nanovaccines with PD-1/PD-L1 blockade. Mater Today Bio. (2024) 27:101136. doi: 10.1016/j.mtbio.2024.101136

PubMed Abstract | Crossref Full Text | Google Scholar

91. Jia X, Yan B, Tian X, Liu Q, Jin J, Shi J, et al. CD47/SIRPα pathway mediates cancer immune escape and immunotherapy. Int J Biol Sci. (2021) 17:3281–7. doi: 10.7150/ijbs.60782

PubMed Abstract | Crossref Full Text | Google Scholar

92. Block MS, Nevala WK, Leontovich AA, and Markovic SN. Differential response of human and mouse dendritic cells to VEGF determines interspecies discrepancies in tumor-mediated TH1/TH2 polarity shift. Clin Cancer Res. (2011) 17:1776–83. doi: 10.1158/1078-0432.CCR-10-2836

PubMed Abstract | Crossref Full Text | Google Scholar

93. Wu MM, Yang YC, Cai YX, Jiang S, Xiao H, Miao C, et al. Anti-CTLA-4 m2a antibody exacerbates cardiac injury in experimental autoimmune myocarditis mice by promoting ccl5-neutrophil infiltration. Adv Sci (Weinh). (2024) 11:e2400486. doi: 10.1002/advs.202400486

PubMed Abstract | Crossref Full Text | Google Scholar

94. Wu X, Pan B, Chu C, Zhang Y, Ma J, Xing Y, et al. CXCL16/CXCR6/TGF-β Feedback loop between M-MDSCs and treg inhibits anti-bacterial immunity during biofilm infection. Adv Sci (Weinh). (2025) 12:e2409537. doi: 10.1002/advs.202409537

PubMed Abstract | Crossref Full Text | Google Scholar

95. Wang J, Zhao X, and Wan YY. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell Mol Immunol. (2023) 20:1002–22. doi: 10.1038/s41423-023-01036-7

PubMed Abstract | Crossref Full Text | Google Scholar

96. Cano Sanchez M, Lancel S, Boulanger E, and Neviere R. Targeting oxidative stress and mitochondrial dysfunction in the treatment of impaired wound healing: A systematic review. Antioxid (Basel Switzerland). (2018) 7:98. doi: 10.3390/antiox7080098

PubMed Abstract | Crossref Full Text | Google Scholar

97. Ukaegbu K, Allen E, and Svoboda KKH. Reactive oxygen species and antioxidants in wound healing: mechanisms and therapeutic potential. Int Wound J. (2025) 22:e70330. doi: 10.1111/iwj.70330

PubMed Abstract | Crossref Full Text | Google Scholar

98. Zhou J, Li M, Chen Q, Li X, Chen L, Dong Z, et al. Programmable probiotics modulate inflammation and gut microbiota for inflammatory bowel disease treatment after effective oral delivery. Nat Commun. (2022) 13:3432. doi: 10.1038/s41467-022-31171-0

PubMed Abstract | Crossref Full Text | Google Scholar

99. Tsukui T, Wolters PJ, and Sheppard D. Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature. (2024) 631:627–34. doi: 10.1038/s41586-024-07660-1

PubMed Abstract | Crossref Full Text | Google Scholar

100. Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y, et al. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics. (2021) 11:1845–63. doi: 10.7150/thno.50905

PubMed Abstract | Crossref Full Text | Google Scholar

101. Shen J, Jiao W, Yang J, Zhuang B, Du S, Wu Y, et al. In situ photocrosslinkable hydrogel treats radiation-induced skin injury by ROS elimination and inflammation regulation. Biomaterials. (2025) 314:122891. doi: 10.1016/j.biomaterials.2024.122891

PubMed Abstract | Crossref Full Text | Google Scholar

102. Li S, Lu Z, Huang Y, Wang Y, Jin Q, Shentu X, et al. Anti-oxidative and anti-inflammatory micelles: break the dry eye vicious cycle. Adv Sci (Weinh). (2022) 9:e2200435. doi: 10.1002/advs.202200435

PubMed Abstract | Crossref Full Text | Google Scholar

103. Li C, Deng C, Wang S, Dong X, Dai B, Guo W, et al. A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization. Redox Biol. (2024) 70:103059. doi: 10.1016/j.redox.2024.103059

PubMed Abstract | Crossref Full Text | Google Scholar

104. Gao Y, Li J, Cheng W, Diao T, Liu H, Bo Y, et al. Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation. Cancer Cell. (2024) 42:1764–1783.e10. doi: 10.1016/j.ccell.2024.08.020

PubMed Abstract | Crossref Full Text | Google Scholar

105. Buechler MB, Pradhan RN, Krishnamurty AT, Cox C, Calviello AK, Wang AW, et al. Cross-tissue organization of the fibroblast lineage. Nature. (2021) 593:575–9. doi: 10.1038/s41586-021-03549-5

PubMed Abstract | Crossref Full Text | Google Scholar

106. Kuo CL, Ponneri Babuharisankar A, Lin YC, Lien HW, Lo YK, Chou HY, et al. Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend? J BioMed Sci. (2022) 29:74. doi: 10.1186/s12929-022-00859-2

PubMed Abstract | Crossref Full Text | Google Scholar

107. Bryant CE, Gay NJ, Heymans S, Sacre S, Schaefer L, and Midwood KS. Advances in Toll-like receptor biology: Modes of activation by diverse stimuli. Crit Rev Biochem Mol Biol. (2015) 50:359–79. doi: 10.3109/10409238.2015.1033511

PubMed Abstract | Crossref Full Text | Google Scholar

108. Basith S, Manavalan B, Yoo TH, Kim SG, and Choi S. Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res. (2012) 35:1297–316. doi: 10.1007/s12272-012-0802-7

PubMed Abstract | Crossref Full Text | Google Scholar

109. Deng L, Zhong G, Wang Q, Zhu Z, and Peng Y. Mulberry leaf and konjac flour compound dietary fiber improves digestion and metabolism in elderly mice with high-fish-protein diet by regulating gut microbiota structure and intestinal tissue repair. Food Chem X. (2024) 22:101295. doi: 10.1016/j.fochx.2024.101295

PubMed Abstract | Crossref Full Text | Google Scholar

110. Matsushita M, Fujita K, Hayashi T, Kayama H, Motooka D, Hase H, et al. Gut microbiota-derived short-chain fatty acids promote prostate cancer growth via IGF1 signaling. Cancer Res. (2021) 81:4014–26. doi: 10.1158/0008-5472.CAN-20-4090

PubMed Abstract | Crossref Full Text | Google Scholar

111. Feitelson MA, Arzumanyan A, Medhat A, and Spector I. Short-chain fatty acids in cancer pathogenesis. Cancer Metastasis Rev. (2023) 42:677–98. doi: 10.1007/s10555-023-10117-y

PubMed Abstract | Crossref Full Text | Google Scholar

112. Abdelli LS, Samsam A, and Naser SA. Propionic acid induces gliosis and neuro-inflammation through modulation of PTEN/AKT pathway in autism spectrum disorder. Sci Rep. (2019) 9:8824. doi: 10.1038/s41598-019-45348-z

PubMed Abstract | Crossref Full Text | Google Scholar

113. Liu R, Ding Y, Xu Y, Wu Q, Chen Y, Yan G, et al. Engineering a dual-function starch-cellulose composite for colon-targeted probiotic delivery and synergistic gut microbiota regulation in type 2 diabetes therapeutics. Pharmaceutics. (2025) 17:663. doi: 10.3390/pharmaceutics17050663

PubMed Abstract | Crossref Full Text | Google Scholar

114. Jenab A, Roghanian R, and Emtiazi G. Bacterial natural compounds with anti-inflammatory and immunomodulatory properties (Mini review). Drug Des Devel Ther. (2020) 14:3787–801. doi: 10.2147/DDDT.S261283

PubMed Abstract | Crossref Full Text | Google Scholar

115. Gutiérrez-Salmerón M, Lucena SR, Chocarro-Calvo A, García-Martínez JM, Martín Orozco RM, and García-Jiménez C. Remodelling of colorectal cancer cell signalling by microbiota and immunity in diabetes. Endocr Relat Cancer. (2021) 28:R173–r190. doi: 10.1530/ERC-20-0315

PubMed Abstract | Crossref Full Text | Google Scholar

116. Castro PR, Bittencourt LFF, Larochelle S, Andrade SP, Mackay CR, Slevin M, et al. GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling. Am J Physiol Heart Circ Physiol. (2021) 320:H1066–h1079. doi: 10.1152/ajpheart.00515.2019

PubMed Abstract | Crossref Full Text | Google Scholar

117. Bilotta AJ, Ma C, Yang W, Yu Y, Yu Y, Zhao X, et al. Propionate enhances cell speed and persistence to promote intestinal epithelial turnover and repair. Cell Mol Gastroenterol Hepatol. (2021) 11:1023–44. doi: 10.1016/j.jcmgh.2020.11.011

PubMed Abstract | Crossref Full Text | Google Scholar

118. Zheng Y, Ren Z, Liu Y, Yan J, Chen C, He Y, et al. T cell interactions with microglia in immune-inflammatory processes of ischemic stroke. Neural Regener Res. (2025) 20:1277–92. doi: 10.4103/NRR.NRR-D-23-01385

PubMed Abstract | Crossref Full Text | Google Scholar

119. Henao Agudelo JS, Braga TT, Amano MT, Cenedeze MA, Cavinato RA, Peixoto-Santos AR, et al. Mesenchymal stromal cell-derived microvesicles regulate an internal pro-inflammatory program in activated macrophages. Front Immunol. (2017) 8:881. doi: 10.3389/fimmu.2017.00881

PubMed Abstract | Crossref Full Text | Google Scholar

120. Grégoire C, Lechanteur C, Briquet A, Baudoux É., Baron F, Louis E, et al. Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases. Aliment Pharmacol Ther. (2017) 45:205–21. doi: 10.1111/apt.13864

PubMed Abstract | Crossref Full Text | Google Scholar

121. Barnig C, Bezema T, Calder PC, Charloux A, Frossard N, Garssen J, et al. Activation of resolution pathways to prevent and fight chronic inflammation: lessons from asthma and inflammatory bowel disease. Front Immunol. (2019) 10:1699. doi: 10.3389/fimmu.2019.01699

PubMed Abstract | Crossref Full Text | Google Scholar

122. Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. (2017) 76:346–54. doi: 10.1136/annrheumdis-2017-eular.3321

PubMed Abstract | Crossref Full Text | Google Scholar

123. Zhu Z, Zhou S, Li S, Gong S, and Zhang Q. Neutrophil extracellular traps in wound healing. Trends Pharmacol Sci. (2024) 45:1033–45. doi: 10.1016/j.tips.2024.09.007

PubMed Abstract | Crossref Full Text | Google Scholar

124. Zhou Z, Deng T, Tao M, Lin L, Sun L, Song X, et al. Snail-inspired AFG/GelMA hydrogel accelerates diabetic wound healing via inflammatory cytokines suppression and macrophage polarization. Biomaterials. (2023) 299:122141. doi: 10.1016/j.biomaterials.2023.122141

PubMed Abstract | Crossref Full Text | Google Scholar

125. Wang XH, Guo W, Qiu W, Ao LQ, Yao MW, Xing W, et al. Fibroblast-like cells Promote Wound Healing via PD-L1-mediated Inflammation Resolution. Int J Biol Sci. (2022) 18:4388–99. doi: 10.7150/ijbs.69890

PubMed Abstract | Crossref Full Text | Google Scholar

126. Kuan CH, Chang L, Ho CY, Tsai CH, Liu YC, Huang WY, et al. Immunomodulatory hydrogel orchestrates pro-regenerative response of macrophages and angiogenesis for chronic wound healing. Biomaterials. (2025) 314:122848. doi: 10.1016/j.biomaterials.2024.122848

PubMed Abstract | Crossref Full Text | Google Scholar

127. Deng Z and Zhang M. Liposozyme for wound healing and inflammation resolution. Nat Nanotechnol. (2024) 19:1083–4. doi: 10.1038/s41565-024-01656-8

PubMed Abstract | Crossref Full Text | Google Scholar

128. Cai Y, Chen K, Liu C, and Qu X. Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns. Bioact Mater. (2023) 28:243–54. doi: 10.1016/j.bioactmat.2023.04.019

PubMed Abstract | Crossref Full Text | Google Scholar

129. Vénéreau E, Ceriotti C, and Bianchi ME. DAMPs from cell death to new life. Front Immunol. (2015) 6:422. doi: 10.3389/fimmu.2015.00422

PubMed Abstract | Crossref Full Text | Google Scholar

130. Simpson DSA and Oliver PL. ROS generation in microglia: understanding oxidative stress and inflammation in neurodegenerative disease. Antioxid (Basel). (2020) 9:743. doi: 10.3390/antiox9080743

PubMed Abstract | Crossref Full Text | Google Scholar

131. Kato J and Svensson CI. Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain. Prog Mol Biol Transl Sci. (2015) 131:251–79. doi: 10.1016/bs.pmbts.2014.11.014

PubMed Abstract | Crossref Full Text | Google Scholar

132. Gong T, Liu L, Jiang W, and Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. (2020) 20:95–112. doi: 10.1038/s41577-019-0215-7

PubMed Abstract | Crossref Full Text | Google Scholar

133. Zhang M and Zhang S. T cells in fibrosis and fibrotic diseases. Front Immunol. (2020) 11:1142. doi: 10.3389/fimmu.2020.01142

PubMed Abstract | Crossref Full Text | Google Scholar

134. Wang N, Liang H, and Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol. (2014) 5:614. doi: 10.3389/fimmu.2014.00614

PubMed Abstract | Crossref Full Text | Google Scholar

135. Walton K, Walker K, Riddle M, Koehn BH, Reff J, Sagatys EM, et al. Dual JAK2/Aurora kinase A inhibition prevents human skin graft rejection by allo-inactivation and ILC2-mediated tissue repair. Am J Transplant. (2022) 22:717–30. doi: 10.1111/ajt.16870

PubMed Abstract | Crossref Full Text | Google Scholar

136. Valatas V, Kolios G, and Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): A co-stimulatory system of cytokines with diverse functions in gut mucosal immunity. Front Immunol. (2019) 10:583. doi: 10.3389/fimmu.2019.00583

PubMed Abstract | Crossref Full Text | Google Scholar

137. Tidball JG. Mechanisms of muscle injury, repair, and regeneration. Compr Physiol. (2011) 1:2029–62. doi: 10.1002/j.2040-4603.2011.tb00387.x

Crossref Full Text | Google Scholar

138. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. (2018) 233:6425–40. doi: 10.1002/jcp.26429

PubMed Abstract | Crossref Full Text | Google Scholar

139. Ma Q. Polarization of immune cells in the pathologic response to inhaled particulates. Front Immunol. (2020) 11:1060. doi: 10.3389/fimmu.2020.01060

PubMed Abstract | Crossref Full Text | Google Scholar

140. Yang QQ, Zhang L, Zhou YL, and Tang JB. Morphological changes of macrophages and their potential contribution to tendon healing. Colloids Surf B Biointerf. (2022) 209:112145. doi: 10.1016/j.colsurfb.2021.112145

PubMed Abstract | Crossref Full Text | Google Scholar

141. Patrono C. The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol. (2015) 66:74–85. doi: 10.1016/j.jacc.2015.05.012

PubMed Abstract | Crossref Full Text | Google Scholar

142. Li Y, Soendergaard C, Bergenheim FH, Aronoff DM, Milne G, Riis LB, et al. COX-2-PGE(2) signaling impairs intestinal epithelial regeneration and associates with TNF inhibitor responsiveness in ulcerative colitis. EBioMedicine. (2018) 36:497–507. doi: 10.1016/j.ebiom.2018.08.040

PubMed Abstract | Crossref Full Text | Google Scholar

143. Li XJ, Huang FZ, Wan Y, Li YS, Zhang WK, Xi Y, et al. Lipopolysaccharide stimulated the migration of NIH3T3 cells through a positive feedback between β-catenin and COX-2. Front Pharmacol. (2018) 9:1487. doi: 10.3389/fphar.2018.01487

PubMed Abstract | Crossref Full Text | Google Scholar

144. Zhong Y, Wei B, Wang W, Chen J, Wu W, Liang L, et al. Single-cell RNA-sequencing identifies bone marrow-derived progenitor cells as a main source of extracellular matrix-producing cells across multiple organ-based fibrotic diseases. Int J Biol Sci. (2024) 20:5027–42. doi: 10.7150/ijbs.98839

PubMed Abstract | Crossref Full Text | Google Scholar

145. Zhao X, Li Y, Yu J, Teng H, Wu S, Wang Y, et al. Role of mitochondria in pathogenesis and therapy of renal fibrosis. Metabolism. (2024) 155:155913. doi: 10.1016/j.metabol.2024.155913

PubMed Abstract | Crossref Full Text | Google Scholar

146. Zhang Y, Wang J, Sun H, Xun Z, He Z, Zhao Y, et al. TWIST1+FAP+ fibroblasts in the pathogenesis of intestinal fibrosis in Crohn’s disease. J Clin Invest. (2024) 134:e179472. doi: 10.1172/JCI179472

PubMed Abstract | Crossref Full Text | Google Scholar

147. Lin S, Wang J, Mukherjee PK, Mao R, West G, Czarnecki D, et al. Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis. Gut. (2024) 73:1110–23. doi: 10.1136/gutjnl-2022-328608

PubMed Abstract | Crossref Full Text | Google Scholar

148. Chen W, Sun Y, Chen S, Ge X, Zhang W, Zhang N, et al. Matrisome gene-based subclassification of patients with liver fibrosis identifies clinical and molecular heterogeneities. Hepatology. (2023) 78:1118–32. doi: 10.1097/HEP.0000000000000423

PubMed Abstract | Crossref Full Text | Google Scholar

149. Yan J, Wang SY, Su Q, Zou MW, Zhou ZY, Shou J, et al. Targeted immunotherapy rescues pulmonary fibrosis by reducing activated fibroblasts and regulating alveolar cell profile. Nat Commun. (2025) 16:3748. doi: 10.1038/s41467-025-59093-7

PubMed Abstract | Crossref Full Text | Google Scholar

150. Tang J, Liu J, Zhou Z, Cui X, Tu H, Jia J, et al. Oral submucous fibrosis: pathogenesis and therapeutic approaches. Int J Oral Sci. (2025) 17:8. doi: 10.1038/s41368-024-00344-6

PubMed Abstract | Crossref Full Text | Google Scholar

151. Sun W, Zhou S, Peng L, Wang W, Liu Y, Wang T, et al. Fatty acid oxidation-glycolysis metabolic transition affects ECM homeostasis in silica-induced pulmonary fibrosis. Adv Sci (Weinh). (2025) 12:e2407134. doi: 10.1002/advs.202407134

PubMed Abstract | Crossref Full Text | Google Scholar

152. Shen H, Huang X, Zhao Y, Wu D, Xue K, Yao J, et al. The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis. Nat Commun. (2022) 13:6030. doi: 10.1038/s41467-022-33800-0

PubMed Abstract | Crossref Full Text | Google Scholar

153. Sharma S, Prathigudupu V, Cable C, Serrano LR, Nerella S, Chen A, et al. Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation. Sci Transl Med. (2025) 17:eads9470. doi: 10.1126/scitranslmed.ads9470

PubMed Abstract | Crossref Full Text | Google Scholar

154. Odell ID, Steach H, Gauld SB, Reinke-Breen L, Karman J, Carr TL, et al. Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis. Sci Immunol. (2022) 7:eabq6691. doi: 10.1126/sciimmunol.abq6691

PubMed Abstract | Crossref Full Text | Google Scholar

155. Long Y, Niu Y, Liang K, and Du Y. Mechanical communication in fibrosis progression. Trends Cell Biol. (2022) 32:70–90. doi: 10.1016/j.tcb.2021.10.002

PubMed Abstract | Crossref Full Text | Google Scholar

156. Feng J, Li Y, Li Y, Yin Q, Li H, Li J, et al. Versican promotes cardiomyocyte proliferation and cardiac repair. Circulation. (2024) 149:1004–15. doi: 10.1161/CIRCULATIONAHA.123.066298

PubMed Abstract | Crossref Full Text | Google Scholar

157. Chen X, Li X, Wu X, Ding Y, Li Y, Zhou G, et al. Integrin beta-like 1 mediates fibroblast-cardiomyocyte crosstalk to promote cardiac fibrosis and hypertrophy. Cardiovasc Res. (2023) 119:1928–41. doi: 10.1093/cvr/cvad104

PubMed Abstract | Crossref Full Text | Google Scholar

158. Balta MG, Papathanasiou E, Blix IJ, and Van Dyke TE. Host modulation and treatment of periodontal disease. J Dent Res. (2021) 100:798–809. doi: 10.1177/0022034521995157

PubMed Abstract | Crossref Full Text | Google Scholar

159. Alnouri MW, Roquid KA, Bonnavion R, Cho H, Heering J, Kwon J, et al. SPMs exert anti-inflammatory and pro-resolving effects through positive allosteric modulation of the prostaglandin EP4 receptor. Proc Natl Acad Sci U.S.A. (2024) 121:e2407130121. doi: 10.1073/pnas.2407130121

PubMed Abstract | Crossref Full Text | Google Scholar

160. Zhang X and Zhang H. Pro-resolving and anti-inflammatory effects of resolvins and protectins in rheumatoid arthritis. Inflammopharmacology. (2023) 31:2995–3004. doi: 10.1007/s10787-023-01343-5

PubMed Abstract | Crossref Full Text | Google Scholar

161. Stenvik Haatveit Å. and Hansen TV. The biosynthetic pathways of the protectins. Prostaglandins Other Lipid Mediat. (2023) 169:106787. doi: 10.1016/j.prostaglandins.2023.106787

PubMed Abstract | Crossref Full Text | Google Scholar

162. Simard M, Nshimiyimana R, Chiang N, Rodriguez AR, Spur BW, and Serhan CN. A potent proresolving mediator 17R-resolvin D2 from human macrophages, monocytes, and saliva. Sci Adv. (2024) 10:eadq4785. doi: 10.1126/sciadv.adq4785

PubMed Abstract | Crossref Full Text | Google Scholar

163. Panigrahy D, Gilligan MM, Serhan CN, and Kashfi K. Resolution of inflammation: An organizing principle in biology and medicine. Pharmacol Ther. (2021) 227:107879. doi: 10.1016/j.pharmthera.2021.107879

PubMed Abstract | Crossref Full Text | Google Scholar

164. Grazda R, Seyfried AN, Maddipati KR, Fredman G, and MacNamara KC. Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice. Cell Death Dis. (2024) 15:324. doi: 10.1038/s41419-024-06705-7

PubMed Abstract | Crossref Full Text | Google Scholar

165. Xie L, Xue F, Cheng C, Sui W, Zhang J, Meng L, et al. Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis. Signal Transduct Target Ther. (2024) 9:273. doi: 10.1038/s41392-024-01977-z

PubMed Abstract | Crossref Full Text | Google Scholar

166. Tang BY, Ge J, Wu Y, Wen J, and Tang XH. The role of ADAM17 in inflammation-related atherosclerosis. J Cardiovasc Transl Res. (2022) 15:1283–96. doi: 10.1007/s12265-022-10275-4

PubMed Abstract | Crossref Full Text | Google Scholar

167. Maute R, Xu J, and Weissman IL. CD47-SIRPα-targeted therapeutics: status and prospects. Immunooncol Technol. (2022) 13:100070. doi: 10.1016/j.iotech.2022.100070

PubMed Abstract | Crossref Full Text | Google Scholar

168. Lakhotia R, Melani C, Pittaluga S, Gordon MJ, Phelan JD, Muppidi JR, et al. The anti-CD47 antibody magrolimab with obinutuzumab and venetoclax in relapsed or refractory indolent B-cell lymphomas. Br J Haematol. (2025) 207:612–8. doi: 10.1111/bjh.20219

PubMed Abstract | Crossref Full Text | Google Scholar

169. Schilperoort M, Ngai D, Katerelos M, Power DA, and Tabas I. PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages. Nat Metab. (2023) 5:431–44. doi: 10.1038/s42255-023-00736-8

PubMed Abstract | Crossref Full Text | Google Scholar

170. Lin J, Xu A, Jin J, Zhang M, Lou J, Qian C, et al. MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression. Oncoimmunology. (2022) 11:2024941. doi: 10.1080/2162402X.2021.2024941

PubMed Abstract | Crossref Full Text | Google Scholar

171. Gerlach BD, Ampomah PB, Yurdagul A Jr., Liu C, Lauring MC, Wang X, et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab. (2021) 33:2445–2463.e8. doi: 10.1016/j.cmet.2021.10.015

PubMed Abstract | Crossref Full Text | Google Scholar

172. Post SM, Andreeff M, DiNardo C, Khoury JD, and Ruvolo PP. TAM kinases as regulators of cell death. Biochim Biophys Acta Mol Cell Res. (2021) 1868:118992. doi: 10.1016/j.bbamcr.2021.118992

PubMed Abstract | Crossref Full Text | Google Scholar

173. Zhu C, Wei Y, and Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. (2019) 18:153. doi: 10.1186/s12943-019-1090-3

PubMed Abstract | Crossref Full Text | Google Scholar

174. Tang Y, Zang H, Wen Q, and Fan S. AXL in cancer: a modulator of drug resistance and therapeutic target. J Exp Clin Cancer Res. (2023) 42:148. doi: 10.1186/s13046-023-02726-w

PubMed Abstract | Crossref Full Text | Google Scholar

175. Lahey KC, Varsanyi C, Wang Z, Aquib A, Gadiyar V, Rodrigues AA, et al. Regulation of mertk surface expression via ADAM17 and γ-secretase proteolytic processing. Int J Mol Sci. (2024) 25:4404. doi: 10.3390/ijms25084404

PubMed Abstract | Crossref Full Text | Google Scholar

176. Cai B, Dongiovanni P, Corey KE, Wang X, Shmarakov IO, Zheng Z, et al. Macrophage merTK promotes liver fibrosis in nonalcoholic steatohepatitis. Cell Metab. (2020) 31:406–421.e7. doi: 10.1016/j.cmet.2019.11.013

PubMed Abstract | Crossref Full Text | Google Scholar

177. Kang JH, Ko HM, Han GD, Lee SY, Moon JS, Kim MS, et al. Dual role of phosphatidylserine and its receptors in osteoclastogenesis. Cell Death Dis. (2020) 11:497. doi: 10.1038/s41419-020-2712-9

PubMed Abstract | Crossref Full Text | Google Scholar

178. Wei J and Gronert K. Eicosanoid and specialized proresolving mediator regulation of lymphoid cells. Trends Biochem Sci. (2019) 44:214–25. doi: 10.1016/j.tibs.2018.10.007

PubMed Abstract | Crossref Full Text | Google Scholar

179. Serhan CN and Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. (2018) 128:2657–69. doi: 10.1172/JCI97943

PubMed Abstract | Crossref Full Text | Google Scholar

180. Serhan CN, Libreros S, and Nshimiyimana R. E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of specialized pro-resolving mediators (SPMs) in inflammation-resolution: Preparing SPMs for long COVID-19, human clinical trials, and targeted precision nutrition. Semin Immunol. (2022) 59:101597. doi: 10.1016/j.smim.2022.101597

PubMed Abstract | Crossref Full Text | Google Scholar

181. Yang WS, Wang JL, Wu W, Wang GF, Yan J, Liu Q, et al. Formyl peptide receptor 2 as a potential therapeutic target for inflammatory bowel disease. Acta Pharmacol Sin. (2023) 44:19–31. doi: 10.1038/s41401-022-00944-0

PubMed Abstract | Crossref Full Text | Google Scholar

182. Powell WS. Eicosanoid receptors as therapeutic targets for asthma. Clin Sci (Lond). (2021) 135:1945–80. doi: 10.1042/CS20190657

PubMed Abstract | Crossref Full Text | Google Scholar

183. Hesselink JM, Chiosi F, and Costagliola C. Resolvins and aliamides: lipid autacoids in ophthalmology - what promise do they hold? Drug Des Devel Ther. (2016) 10:3133–41. doi: 10.2147/DDDT.S112389

PubMed Abstract | Crossref Full Text | Google Scholar

184. Xu X, Gao W, Li L, Hao J, Yang B, Wang T, et al. Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway. J Neuroinflamm. (2021) 18:119. doi: 10.1186/s12974-021-02174-3

PubMed Abstract | Crossref Full Text | Google Scholar

185. Chiang N and Serhan CN. Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem. (2020) 64:443–62. doi: 10.1042/EBC20200018

PubMed Abstract | Crossref Full Text | Google Scholar

186. Barden AE, Mas E, and Mori TA. n-3 Fatty acid supplementation and proresolving mediators of inflammation. Curr Opin Lipidol. (2016) 27:26–32. doi: 10.1097/MOL.0000000000000262

PubMed Abstract | Crossref Full Text | Google Scholar

187. Cutolo M, Campitiello R, Gotelli E, and Soldano S. The role of M1/M2 macrophage polarization in rheumatoid arthritis synovitis. Front Immunol. (2022) 13:867260. doi: 10.3389/fimmu.2022.867260

PubMed Abstract | Crossref Full Text | Google Scholar

188. Cao M, Yan H, Han X, Weng L, Wei Q, Sun X, et al. Ginseng-derived nanoparticles alter macrophage polarization to inhibit melanoma growth. J Immunother Cancer. (2019) 7:326. doi: 10.1186/s40425-019-0817-4

PubMed Abstract | Crossref Full Text | Google Scholar

189. Atta AA, Ibrahim WW, Mohamed AF, and Abdelkader NF. Microglia polarization in nociplastic pain: mechanisms and perspectives. Inflammopharmacology. (2023) 31:1053–67. doi: 10.1007/s10787-023-01216-x

PubMed Abstract | Crossref Full Text | Google Scholar

190. Zhang L, Wei X, Wang Z, Liu P, Hou Y, Xu Y, et al. NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking. Cell Rep. (2023) 42:112185. doi: 10.1016/j.celrep.2023.112185

PubMed Abstract | Crossref Full Text | Google Scholar

191. Nouri Y, Weinkove R, and Perret R. T-cell intrinsic Toll-like receptor signaling: implications for cancer immunotherapy and CAR T-cells. J Immunother Cancer. (2021) 9:e003065. doi: 10.1136/jitc-2021-003065

PubMed Abstract | Crossref Full Text | Google Scholar

192. Murgueitio MS, Rakers C, Frank A, and Wolber G. Balancing inflammation: computational design of small-molecule toll-like receptor modulators. Trends Pharmacol Sci. (2017) 38:155–68. doi: 10.1016/j.tips.2016.10.007

PubMed Abstract | Crossref Full Text | Google Scholar

193. Song Y, Li P, Qin L, Xu Z, Jiang B, Ma C, et al. CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription. Cell Mol Immunol. (2021) 18:339–49. doi: 10.1038/s41423-019-0323-0

PubMed Abstract | Crossref Full Text | Google Scholar

194. Sun G, Liu H, Zhao J, Zhang J, Huang T, Sun G, et al. Macrophage GSK3β-deficiency inhibits the progression of hepatocellular carcinoma and enhances the sensitivity of anti-PD1 immunotherapy. J Immunother Cancer. (2022) 10:e005655. doi: 10.1136/jitc-2022-005655

PubMed Abstract | Crossref Full Text | Google Scholar

195. Arumugam S, Qin Y, Liang Z, Han SN, Boodapati SLT, Li J, et al. GSK3β mediates the spatiotemporal dynamics of NLRP3 inflammasome activation. Cell Death Differ. (2022) 29:2060–9. doi: 10.1038/s41418-022-00997-y

PubMed Abstract | Crossref Full Text | Google Scholar

196. Hesselbarth R, Esser TU, Roshanbinfar K, Schrüfer S, Schubert DW, and Engel FB. CHIR99021 promotes hiPSC-derived cardiomyocyte proliferation in engineered 3D microtissues. Adv Healthc Mater. (2021) 10:e2100926. doi: 10.1002/adhm.202100926

PubMed Abstract | Crossref Full Text | Google Scholar

197. Buikema JW, Lee S, Goodyer WR, Maas RG, Chirikian O, Li G, et al. Wnt activation and reduced cell-cell contact synergistically induce massive expansion of functional human iPSC-derived cardiomyocytes. Cell Stem Cell. (2020) 27:50–63.e5. doi: 10.1016/j.stem.2020.06.001

PubMed Abstract | Crossref Full Text | Google Scholar

198. Jiang M, Zhang X, Yan X, Mizutani S, Kashiwazaki H, Ni J, et al. GSK3β is involved in promoting Alzheimer’s disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor protein(NL-F/NL-F) knock-in mice. Brain Behav Immun. (2021) 98:1–12. doi: 10.1016/j.bbi.2021.08.213

PubMed Abstract | Crossref Full Text | Google Scholar

199. Irizarry-Caro RA, McDaniel MM, Overcast GR, Jain VG, Troutman TD, and Pasare C. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc Natl Acad Sci U.S.A. (2020) 117:30628–38. doi: 10.1073/pnas.2009778117

PubMed Abstract | Crossref Full Text | Google Scholar

200. Leu CM. Nck, a missing adaptor between the B-cell receptor complex and the BCAP/PI3K/Akt pathway. Cell Mol Immunol. (2014) 11:120–2. doi: 10.1038/cmi.2013.53

PubMed Abstract | Crossref Full Text | Google Scholar

201. Deason K, Troutman TD, Jain A, Challa DK, Mandraju R, Brewer T, et al. BCAP links IL-1R to the PI3K-mTOR pathway and regulates pathogenic Th17 cell differentiation. J Exp Med. (2018) 215:2413–28. doi: 10.1084/jem.20171810

PubMed Abstract | Crossref Full Text | Google Scholar

202. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, Part 1. Ann Rheum Dis. (2014) 73:101–7. doi: 10.1136/annrheumdis-2012-203201

PubMed Abstract | Crossref Full Text | Google Scholar

203. Huang Z, Chen G, and Shi P. Emodin-induced apoptosis in human breast cancer BCap-37 cells through the mitochondrial signaling pathway. Arch Pharm Res. (2008) 31:742–8. doi: 10.1007/s12272-001-1221-6

PubMed Abstract | Crossref Full Text | Google Scholar

204. Dai G, Zheng W, Ma X, and Wang P. Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells. BioMed Pharmacother. (2015) 69:111–8. doi: 10.1016/j.biopha.2014.11.015

PubMed Abstract | Crossref Full Text | Google Scholar

205. Miao Y, Jiang M, Qi L, Yang D, Xiao W, and Fang F. BCAP regulates dendritic cell maturation through the dual-regulation of NF-κB and PI3K/AKT signaling during infection. Front Immunol. (2020) 11:250. doi: 10.3389/fimmu.2020.00250

PubMed Abstract | Crossref Full Text | Google Scholar

206. Troutman TD, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan JF, et al. Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci U.S.A. (2012) 109:273–8. doi: 10.1073/pnas.1118579109

PubMed Abstract | Crossref Full Text | Google Scholar

207. Yahfoufi N, Alsadi N, Jambi M, and Matar C. The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients. (2018) 10:1618. doi: 10.3390/nu10111618

PubMed Abstract | Crossref Full Text | Google Scholar

208. Kumar R, Theiss AL, and Venuprasad K. RORγt protein modifications and IL-17-mediated inflammation. Trends Immunol. (2021) 42:1037–50. doi: 10.1016/j.it.2021.09.005

PubMed Abstract | Crossref Full Text | Google Scholar

209. Sundaram B, Pandian N, Kim HJ, Abdelaal HM, Mall R, Indari O, et al. NLRC5 senses NAD(+) depletion, forming a PANoptosome and driving PANoptosis and inflammation. Cell. (2024) 187:4061–4077.e17. doi: 10.1016/j.cell.2024.05.034

PubMed Abstract | Crossref Full Text | Google Scholar

210. Luo Q, Zhang Q, Kong Y, Wang S, and Wei Q. Heart failure, inflammation and exercise. Int J Biol Sci. (2025) 21:3324–50. doi: 10.7150/ijbs.109917

PubMed Abstract | Crossref Full Text | Google Scholar

211. Larabi A, Barnich N, and Nguyen HTT. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy. (2020) 16:38–51. doi: 10.1080/15548627.2019.1635384

PubMed Abstract | Crossref Full Text | Google Scholar

212. Huang F, Gu J, Zhu P, Bao C, Xu J, Xu H, et al. Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: results of a randomised, controlled trial. Ann Rheum Dis. (2014) 73:587–94. doi: 10.1136/annrheumdis-2012-202533

PubMed Abstract | Crossref Full Text | Google Scholar

213. Wang L and He C. Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol. (2022) 13:967193. doi: 10.3389/fimmu.2022.967193

PubMed Abstract | Crossref Full Text | Google Scholar

214. Ward R, Li W, Abdul Y, Jackson L, Dong G, Jamil S, et al. NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia. Pharmacol Res. (2019) 142:237–50. doi: 10.1016/j.phrs.2019.01.035

PubMed Abstract | Crossref Full Text | Google Scholar

215. Pan P, Shen M, Yu Z, Ge W, Chen K, Tian M, et al. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat Commun. (2021) 12:4664. doi: 10.1038/s41467-021-25015-6

PubMed Abstract | Crossref Full Text | Google Scholar

216. Tall AR and Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. (2015) 15:104–16. doi: 10.1038/nri3793

PubMed Abstract | Crossref Full Text | Google Scholar

217. Hoque R, Farooq A, Ghani A, Gorelick F, and Mehal WZ. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology. (2014) 146:1763–74. doi: 10.1053/j.gastro.2014.03.014

PubMed Abstract | Crossref Full Text | Google Scholar

218. Zhang Y, Zhang S, Li B, Luo Y, Gong Y, Jin X, et al. Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome. Cardiovasc Res. (2022) 118:785–97. doi: 10.1093/cvr/cvab114

PubMed Abstract | Crossref Full Text | Google Scholar

219. Man SM. Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. Nat Rev Gastroenterol Hepatol. (2018) 15:721–37. doi: 10.1038/s41575-018-0054-1

PubMed Abstract | Crossref Full Text | Google Scholar

220. Jackson DN and Theiss AL. Gut bacteria signaling to mitochondria in intestinal inflammation and cancer. Gut Microbes. (2020) 11:285–304. doi: 10.1080/19490976.2019.1592421

PubMed Abstract | Crossref Full Text | Google Scholar

221. Guggino G, Mauro D, Rizzo A, Alessandro R, Raimondo S, Bergot AS, et al. Inflammasome activation in ankylosing spondylitis is associated with gut dysbiosis. Arthritis Rheumatol. (2021) 73:1189–99. doi: 10.1002/art.41644

PubMed Abstract | Crossref Full Text | Google Scholar

222. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. (2015) 21:248–55. doi: 10.1038/nm.3806

PubMed Abstract | Crossref Full Text | Google Scholar

223. Franke M, Bieber M, Kraft P, Weber ANR, Stoll G, and Schuhmann MK. The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun. (2021) 92:223–33. doi: 10.1016/j.bbi.2020.12.009

PubMed Abstract | Crossref Full Text | Google Scholar

224. Yao C, Veleva T, Scott L Jr., Cao S, Li L, Chen G, et al. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation. (2018) 138:2227–42. doi: 10.1161/CIRCULATIONAHA.118.035202

PubMed Abstract | Crossref Full Text | Google Scholar

225. Zeng W, Wu D, Sun Y, Suo Y, Yu Q, Zeng M, et al. The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages. Sci Rep. (2021) 11:19305. doi: 10.1038/s41598-021-98437-3

PubMed Abstract | Crossref Full Text | Google Scholar

226. Li H, Guan Y, Liang B, Ding P, Hou X, Wei W, et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. Eur J Pharmacol. (2022) 928:175091. doi: 10.1016/j.ejphar.2022.175091

PubMed Abstract | Crossref Full Text | Google Scholar

227. Saber S, Youssef ME, Sharaf H, Amin NA, El-Shedody R, Aboutouk FH, et al. BBG enhances OLT1177-induced NLRP3 inflammasome inactivation by targeting P2X7R/NLRP3 and MyD88/NF-κB signaling in DSS-induced colitis in rats. Life Sci. (2021) 270:119123. doi: 10.1016/j.lfs.2021.119123

PubMed Abstract | Crossref Full Text | Google Scholar

228. Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. (2017) 214:3219–38. doi: 10.1084/jem.20171419

PubMed Abstract | Crossref Full Text | Google Scholar

229. He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun. (2018) 9:2550. doi: 10.1038/s41467-018-04947-6

PubMed Abstract | Crossref Full Text | Google Scholar

230. Xu J and Núñez G. The NLRP3 inflammasome: activation and regulation. Trends Biochem Sci. (2023) 48:331–44. doi: 10.1016/j.tibs.2022.10.002

Crossref Full Text | Google Scholar

231. Su P, Mao X, Ma J, Huang L, Yu L, Tang S, et al. ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer. J Exp Clin Cancer Res. (2023) 42:274. doi: 10.1186/s13046-023-02834-7

PubMed Abstract | Crossref Full Text | Google Scholar

232. Chen Z, Chen H, Huang W, Guo X, Yu L, Shan J, et al. Bacteroides fragilis alleviates necrotizing enterocolitis through restoring bile acid metabolism balance using bile salt hydrolase and inhibiting FXR-NLRP3 signaling pathway. Gut Microbes. (2024) 16:2379566. doi: 10.1080/19490976.2024.2379566

PubMed Abstract | Crossref Full Text | Google Scholar

233. Wu K, Yuan Y, Yu H, Dai X, Wang S, Sun Z, et al. The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice. Blood. (2020) 136:501–15. doi: 10.1182/blood.2019003990

PubMed Abstract | Crossref Full Text | Google Scholar

234. Martinez FO and Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. (2014) 6:13. doi: 10.12703/P6-13

PubMed Abstract | Crossref Full Text | Google Scholar

235. Wang Y, Chen W, Qiao S, Zou H, Yu XJ, Yang Y, et al. Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma. Cell Mol Immunol. (2024) 21:1120–30. doi: 10.1038/s41423-024-01199-x

PubMed Abstract | Crossref Full Text | Google Scholar

236. Xie M, Lin Z, Ji X, Luo X, Zhang Z, Sun M, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol. (2023) 79:109–25. doi: 10.1016/j.jhep.2023.02.036

PubMed Abstract | Crossref Full Text | Google Scholar

237. Hou J, Zhao R, Xia W, Chang CW, You Y, Hsu JM, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol. (2020) 22:1264–75. doi: 10.1038/s41556-020-0575-z

PubMed Abstract | Crossref Full Text | Google Scholar

238. Chen J, Feng W, Sun M, Huang W, Wang G, Chen X, et al. TGF-β1-induced SOX18 elevation promotes hepatocellular carcinoma progression and metastasis through transcriptionally upregulating PD-L1 and CXCL12. Gastroenterology. (2024) 167:264–80. doi: 10.1053/j.gastro.2024.02.025

PubMed Abstract | Crossref Full Text | Google Scholar

239. Mori S, Kohyama M, Yasumizu Y, Tada A, Tanzawa K, Shishido T, et al. Neoself-antigens are the primary target for autoreactive T cells in human lupus. Cell. (2024) 187:6071–6087.e20. doi: 10.1016/j.cell.2024.08.025

PubMed Abstract | Crossref Full Text | Google Scholar

240. Axelrod ML, Cook RS, Johnson DB, and Balko JM. Biological consequences of MHC-II expression by tumor cells in cancer. Clin Cancer Res. (2019) 25:2392–402. doi: 10.1158/1078-0432.CCR-18-3200

PubMed Abstract | Crossref Full Text | Google Scholar

241. Wik JA and Skålhegg BS. T cell metabolism in infection. Front Immunol. (2022) 13:840610. doi: 10.3389/fimmu.2022.840610

PubMed Abstract | Crossref Full Text | Google Scholar

242. Saravia J, Chapman NM, and Chi H. Helper T cell differentiation. Cell Mol Immunol. (2019) 16:634–43. doi: 10.1038/s41423-019-0220-6

PubMed Abstract | Crossref Full Text | Google Scholar

243. Srinivas US, Tan BWQ, Vellayappan BA, and Jeyasekharan AD. ROS and the DNA damage response in cancer. Redox Biol. (2019) 25:101084. doi: 10.1016/j.redox.2018.101084

PubMed Abstract | Crossref Full Text | Google Scholar

244. Schieber M and Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. (2014) 24:R453–62. doi: 10.1016/j.cub.2014.03.034

PubMed Abstract | Crossref Full Text | Google Scholar

245. Xiang Q, Zhao Y, Lin J, Jiang S, and Li W. The Nrf2 antioxidant defense system in intervertebral disc degeneration: Molecular insights. Exp Mol Med. (2022) 54:1067–75. doi: 10.1038/s12276-022-00829-6

PubMed Abstract | Crossref Full Text | Google Scholar

246. Lu MC, Ji JA, Jiang ZY, and You QD. The keap1-nrf2-ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev. (2016) 36:924–63. doi: 10.1002/med.21396

PubMed Abstract | Crossref Full Text | Google Scholar

247. Adinolfi S, Patinen T, Jawahar Deen A, Pitkänen S, Härkönen J, Kansanen E, et al. The KEAP1-NRF2 pathway: Targets for therapy and role in cancer. Redox Biol. (2023) 63:102726. doi: 10.1016/j.redox.2023.102726

PubMed Abstract | Crossref Full Text | Google Scholar

248. Zhang Z, Qu J, Zheng C, Zhang P, Zhou W, Cui W, et al. Nrf2 antioxidant pathway suppresses Numb-mediated epithelial-mesenchymal transition during pulmonary fibrosis. Cell Death Dis. (2018) 9:83. doi: 10.1038/s41419-017-0198-x

PubMed Abstract | Crossref Full Text | Google Scholar

249. Ross D and Siegel D. The diverse functionality of NQO1 and its roles in redox control. Redox Biol. (2021) 41:101950. doi: 10.1016/j.redox.2021.101950

PubMed Abstract | Crossref Full Text | Google Scholar

250. Hooftman A, Angiari S, Hester S, Corcoran SE, Runtsch MC, Ling C, et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab. (2020) 32:468–478.e7. doi: 10.1016/j.cmet.2020.07.016

PubMed Abstract | Crossref Full Text | Google Scholar

251. Xu L, Cai J, Li C, Yang M, Duan T, Zhao Q, et al. 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling. Mol Med. (2023) 29:58. doi: 10.1186/s10020-023-00631-8

PubMed Abstract | Crossref Full Text | Google Scholar

252. Li T, Li JW, Qin YH, Liu R, Xu XN, Li X, et al. 4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders. Ann Clin Transl Neurol. (2024) 11:1732–1749. doi: 10.1002/acn3.52080

PubMed Abstract | Crossref Full Text | Google Scholar

253. Eser A, Colombel JF, Rutgeerts P, Vermeire S, Vogelsang H, Braddock M, et al. Safety and efficacy of an oral inhibitor of the purinergic receptor P2X7 in adult patients with moderately to severely active crohn’s disease: A randomized placebo-controlled, double-blind, phase IIa study. Inflammation Bowel Dis. (2015) 21:2247–53. doi: 10.1097/MIB.0000000000000514

PubMed Abstract | Crossref Full Text | Google Scholar

254. Keystone EC, Wang MM, Layton M, Hollis S, and McInnes IB. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis. (2012) 71:1630–5. doi: 10.1136/annrheumdis-2011-143578

PubMed Abstract | Crossref Full Text | Google Scholar

255. Yasuda K, Takeuchi Y, and Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol. (2019) 41:283–97. doi: 10.1007/s00281-019-00733-8

PubMed Abstract | Crossref Full Text | Google Scholar

256. Schnell A, Huang L, Singer M, Singaraju A, Barilla RM, Regan BML, et al. Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity. Cell. (2021) 184:6281–6298.e23. doi: 10.1016/j.cell.2021.11.018

PubMed Abstract | Crossref Full Text | Google Scholar

257. Miossec P and Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. (2012) 11:763–76. doi: 10.1038/nrd3794

PubMed Abstract | Crossref Full Text | Google Scholar

258. Liu T, Li S, Ying S, Tang S, Ding Y, Li Y, et al. The IL-23/IL-17 pathway in inflammatory skin diseases: from bench to bedside. Front Immunol. (2020) 11:594735. doi: 10.3389/fimmu.2020.594735

PubMed Abstract | Crossref Full Text | Google Scholar

259. Xu H, Wu L, Nguyen HH, Mesa KR, Raghavan V, Episkopou V, et al. Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation. J Exp Med. (2021) 218:e20210777. doi: 10.1084/jem.20210777

PubMed Abstract | Crossref Full Text | Google Scholar

260. Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. (2016) 22:679–84. doi: 10.1038/nm.4086

PubMed Abstract | Crossref Full Text | Google Scholar

261. Kanamori M, Nakatsukasa H, Okada M, Lu Q, and Yoshimura A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol. (2016) 37:803–11. doi: 10.1016/j.it.2016.08.012

PubMed Abstract | Crossref Full Text | Google Scholar

262. Lee GR. The balance of th17 versus treg cells in autoimmunity. Int J Mol Sci. (2018) 19:730. doi: 10.3390/ijms19030730

PubMed Abstract | Crossref Full Text | Google Scholar

263. Korn T, Bettelli E, Oukka M, and Kuchroo VK. IL-17 and th17 cells. Annu Rev Immunol. (2009) 27:485–517. doi: 10.1146/annurev.immunol.021908.132710

PubMed Abstract | Crossref Full Text | Google Scholar

264. Gaffen SL, Jain R, Garg AV, and Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. (2014) 14:585–600. doi: 10.1038/nri3707

PubMed Abstract | Crossref Full Text | Google Scholar

265. Sarin R, Gu R, Jalali Z, Maverakis E, Tsokos MG, and Adamopoulos IE. IL-27 attenuates IL-23 mediated inflammatory arthritis. Clin Immunol. (2023) 251:109327. doi: 10.1016/j.clim.2023.109327

PubMed Abstract | Crossref Full Text | Google Scholar

266. Maloy KJ and Kullberg MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. (2008) 1:339–49. doi: 10.1038/mi.2008.28

PubMed Abstract | Crossref Full Text | Google Scholar

267. Abraham C and Cho JH. IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med. (2009) 60:97–110. doi: 10.1146/annurev.med.60.051407.123757

PubMed Abstract | Crossref Full Text | Google Scholar

268. Pedersen SJ and Maksymowych WP. Beyond the TNF-α Inhibitors: new and emerging targeted therapies for patients with axial spondyloarthritis and their relation to pathophysiology. Drugs. (2018) 78:1397–418. doi: 10.1007/s40265-018-0971-x

PubMed Abstract | Crossref Full Text | Google Scholar

269. Nogueira M, Warren RB, and Torres T. Risk of tuberculosis reactivation with interleukin (IL)-17 and IL-23 inhibitors in psoriasis - time for a paradigm change. J Eur Acad Dermatol Venereol. (2021) 35:824–34. doi: 10.1111/jdv.16866

PubMed Abstract | Crossref Full Text | Google Scholar

270. Glatt S, Baeten D, Baker T, Griffiths M, Ionescu L, Lawson ADG, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann Rheum Dis. (2018) 77:523–32. doi: 10.1136/annrheumdis-2017-212127

PubMed Abstract | Crossref Full Text | Google Scholar

271. van der Heijde D, Cheng-Chung Wei J, Dougados M, Mease P, Deodhar A, Maksymowych WP, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. (2018) 392:2441–51. doi: 10.1016/S0140-6736(18)31946-9

PubMed Abstract | Crossref Full Text | Google Scholar

272. Sands BE, Irving PM, Hoops T, Izanec JL, Gao LL, Gasink C, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet. (2022) 399:2200–11. doi: 10.1016/S0140-6736(22)00688-2

PubMed Abstract | Crossref Full Text | Google Scholar

273. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for crohn’s disease. N Engl J Med. (2016) 375:1946–60. doi: 10.1056/NEJMoa1602773

PubMed Abstract | Crossref Full Text | Google Scholar

274. Poddubnyy D, Hermann KG, Callhoff J, Listing J, and Sieper J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis. (2014) 73:817–23. doi: 10.1136/annrheumdis-2013-204248

PubMed Abstract | Crossref Full Text | Google Scholar

275. McCormack PL. Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Drugs. (2011) 71:2457–89. doi: 10.2165/11208240-000000000-00000

PubMed Abstract | Crossref Full Text | Google Scholar

276. Croom KF and Siddiqui MA. Etoricoxib: a review of its use in the symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis. Drugs. (2009) 69:1513–32. doi: 10.2165/00003495-200969110-00008

PubMed Abstract | Crossref Full Text | Google Scholar

277. Saviano A, Raucci F, Casillo GM, Mansour AA, Piccolo V, Montesano C, et al. Anti-inflammatory and immunomodulatory activity of Mangifera indica L. reveals the modulation of COX-2/mPGES-1 axis and Th17/Treg ratio. Pharmacol Res. (2022) 182:106283. doi: 10.1016/j.phrs.2022.106283

PubMed Abstract | Crossref Full Text | Google Scholar

278. Lin X, Sun Q, Zhou L, He M, Dong X, Lai M, et al. Colonic epithelial mTORC1 promotes ulcerative colitis through COX-2-mediated Th17 responses. Mucosal Immunol. (2018) 11:1663–73. doi: 10.1038/s41385-018-0018-3

PubMed Abstract | Crossref Full Text | Google Scholar

279. Kroon FP, van der Burg LR, Ramiro S, Landewé RB, Buchbinder R, Falzon L, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis). Cochrane Database Syst Rev. (2015) 2015:Cd010952. doi: 10.1002/14651858.CD010952.pub2

PubMed Abstract | Crossref Full Text | Google Scholar

280. Roozbehkia M, Mahmoudi M, Aletaha S, Rezaei N, Fattahi MJ, Jafarnezhad-Ansariha F, et al. The potent suppressive effect of β-d-mannuronic acid (M2000) on molecular expression of the TLR/NF-kB Signaling Pathway in ankylosing spondylitis patients. Int Immunopharmacol. (2017) 52:191–6. doi: 10.1016/j.intimp.2017.08.018

PubMed Abstract | Crossref Full Text | Google Scholar

281. Jafarnezhad-Ansariha F, Yekaninejad MS, Jamshidi AR, Mansouri R, Vojdanian M, Mahmoudi M, et al. The effects of β-D-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line. Inflammopharmacology. (2018) 26:375–84. doi: 10.1007/s10787-017-0386-4

PubMed Abstract | Crossref Full Text | Google Scholar

282. Mohsenzadegan M, Moghbeli F, Mirshafiey A, and Farajollahi MM. Anti-tumor effect of M2000 (β-d-mannuronic acid) on the expression of inflammatory molecules in the prostate cancer cell. Immunopharmacol Immunotoxicol. (2021) 43:419–30. doi: 10.1080/08923973.2021.1931301

PubMed Abstract | Crossref Full Text | Google Scholar

283. Mirshafiey A, Taeb M, Mortazavi-Jahromi SS, Jafarnezhad-Ansariha F, Rehm BHA, Esposito E, et al. Introduction of β-d-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property based on COX-1/COX-2 activity and gene expression. Pharmacol Rep. (2017) 69:1067–72. doi: 10.1016/j.pharep.2017.04.015

PubMed Abstract | Crossref Full Text | Google Scholar

284. Landén NX, Li D, and Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci: CMLS. (2016) 73:3861–85. doi: 10.1007/s00018-016-2268-0

PubMed Abstract | Crossref Full Text | Google Scholar

285. Laurent P, Jolivel V, Manicki P, Chiu L, Contin-Bordes C, Truchetet ME, et al. Immune-mediated repair: A matter of plasticity. Front Immunol. (2017) 8:454. doi: 10.3389/fimmu.2017.00454

PubMed Abstract | Crossref Full Text | Google Scholar

286. Liu J, Zhang Y, Liu C, Jiang Y, Wang Z, Guo Z, et al. A single dose of VEGF-A circular RNA sustains in situ long-term expression of protein to accelerate diabetic wound healing. J Controlled Release: Off J Controlled Release Soc. (2024) 373:319–35. doi: 10.1016/j.jconrel.2024.07.018

PubMed Abstract | Crossref Full Text | Google Scholar

287. Shi A, Li J, Qiu X, Sabbah M, Boroumand S, Huang TC, et al. TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo. Theranostics. (2021) 11:6616–31. doi: 10.7150/thno.57701

PubMed Abstract | Crossref Full Text | Google Scholar

288. Wang Y, Wang J, Zhang J, Wang Y, Wang Y, Kang H, et al. Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis. Sci Adv. (2024) 10:eadj3289. doi: 10.1126/sciadv.adj3289

PubMed Abstract | Crossref Full Text | Google Scholar

289. Soták M, Clark M, Suur BE, and Börgeson E. Inflammation and resolution in obesity. Nat Rev Endocrinol. (2025) 21:45–61. doi: 10.1038/s41574-024-01047-y

PubMed Abstract | Crossref Full Text | Google Scholar

290. Hsu AY, Huang Q, Pi X, Fu J, Raghunathan K, Ghimire L, et al. Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution. Cell. (2025) 188:1623–1641.e26. doi: 10.1016/j.cell.2025.01.021

PubMed Abstract | Crossref Full Text | Google Scholar

291. Sha Y, Wang S, Bocci F, Zhou P, and Nie Q. Inference of intercellular communications and multilayer gene-regulations of epithelial-mesenchymal transition from single-cell transcriptomic data. Front Genet. (2020) 11:604585. doi: 10.3389/fgene.2020.604585

PubMed Abstract | Crossref Full Text | Google Scholar

292. Smith TD, Nagalla RR, Chen EY, and Liu WF. Harnessing macrophage plasticity for tissue regeneration. Adv Drug Delivery Rev. (2017) 114:193–205. doi: 10.1016/j.addr.2017.04.012

PubMed Abstract | Crossref Full Text | Google Scholar

293. Sheetz M. A tale of two states: normal and transformed, with and without rigidity sensing. Annu Rev Cell Dev Biol. (2019) 35:169–90. doi: 10.1146/annurev-cellbio-100818-125227

PubMed Abstract | Crossref Full Text | Google Scholar

294. Jin Y, Li S, Yu Q, Chen T, and Liu D. Application of stem cells in regeneration medicine. MedComm (2020). (2023) 4:e291. doi: 10.1002/mco2.291

PubMed Abstract | Crossref Full Text | Google Scholar

295. Minjares M, Thepsuwan P, Zhang K, and Wang JM. Unfolded protein responses: Dynamic machinery in wound healing. Pharmacol Ther. (2025) 267:108798. doi: 10.1016/j.pharmthera.2025.108798

PubMed Abstract | Crossref Full Text | Google Scholar

296. Lu YZ, Nayer B, Singh SK, Alshoubaki YK, Yuan E, Park AJ, et al. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature. (2024) 628:604–11. doi: 10.1038/s41586-024-07237-y

PubMed Abstract | Crossref Full Text | Google Scholar

297. Li J, Wang X, Yao Z, Yuan F, Liu H, Sun Z, et al. NLRP3-dependent crosstalk between pyroptotic macrophage and senescent cell orchestrates trauma-induced heterotopic ossification during aberrant wound healing. Adv Sci (Weinh). (2023) 10:e2207383. doi: 10.1002/advs.202207383

PubMed Abstract | Crossref Full Text | Google Scholar

298. Butin-Israeli V, Bui TM, Wiesolek HL, Mascarenhas L, Lee JJ, Mehl LC, et al. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. J Clin Invest. (2019) 129:712–26. doi: 10.1172/JCI122085

PubMed Abstract | Crossref Full Text | Google Scholar

299. Brauer E, Lippens E, Klein O, Nebrich G, Schreivogel S, Korus G, et al. Collagen fibrils mechanically contribute to tissue contraction in an in vitro wound healing scenario. Adv Sci (Weinh). (2019) 6:1801780. doi: 10.1002/advs.201801780

PubMed Abstract | Crossref Full Text | Google Scholar

300. Bartold M and Ivanovski S. Biological processes and factors involved in soft and hard tissue healing. Periodontol. (2025) 2000 97:16–42. doi: 10.1111/prd.12546

PubMed Abstract | Crossref Full Text | Google Scholar