Role of toll-like receptors in pulmonary immunity: mechanisms and therapeutic implications

Toll-like receptors (TLRs) belong to the family of pattern recognition receptors (PRRs), playing critical roles in linking innate with adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). TLRs and TLR signaling pathways serve as not only the first line of pulmonary defense against pathogens infection but crucial factors in maintaining pulmonary immune homeostasis. However, aberrant activation of TLR signaling leads to inflammation and immune dysregulations, contributing to various pulmonary diseases, including inflammation, infection, fibrosis, and malignancy. This review summarizes the updated roles of TLRs and TLR signaling in lung development and the establishment and regulation of pulmonary region-specific immunity. We further elucidate the involvement of TLRs and TLR signaling in the onset and progression of lung diseases, such as infections, fibrosis, malignancies, and immune disorders. It would provide updated insights into the exploration of novel diagnostic and therapeutic strategies targeting TLRs and TLR signaling in pulmonary diseases.

1 Introduction

Toll-like receptors (TLRs) belong to the family of pattern recognition receptors (PRRs) that primarily recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) and activate innate immune response. They play pivotal roles in immune defense, inflammatory response, and the linkage of innate immunity with adaptive immunity. This receptor family was named due to its structural similarity to the Drosophila “Toll” protein firstly identified by Eric Wieschaus and Christiane Nüsslein-Volhard during Drosophila developmental research (1). Subsequently, TLRs have been found to be closely associated with inflammatory and immune responses (2, 3). The murine genome encodes a total of 12 functional Tlrs, comprising Tlr1 through Tlr9 along with Tlr11 to Tlr13. Notably, the expression of functional Tlr10 is absent in mice due to the insertion of retroviral-derived DNA sequences that disrupt its coding region (4). Among humans, ten functional TLRs have been identified, designated as TLR1 through TLR10 (4). Based on their distinct subcellular localization patterns, TLRs can be categorized into two principal subfamilies including the cell surface subfamily and the endosomal subfamily (5). The cell surface subfamily, comprising TLR1, TLR2, TLR4, TLR5, and TLR6, is primarily localized to the plasma membrane, where these receptors recognize lipids, lipoproteins, and other extracellular PAMPs. In contrast, the endosomal subfamily, which includes TLR3, TLR7, TLR8, and TLR9, predominantly resides within intracellular compartments, such as the endoplasmic reticulum, endosomes, and lysosomes, where they mediate the detection of nucleic acids derived from intracellular pathogens (5).

From a molecular perspective, TLRs are type I single-pass transmembrane proteins, ranging from 700 to 1, 100 amino acids in length, whose extracellular leucine-rich repeat (LRR) domains serve as sensors for PAMPs, thereby triggering the activation of innate immunity (6, 7). The intracellular Toll/IL-1 receptor (TIR) domain is evolutionarily conserved and serves as a signaling platform for the recruitment of specific adaptor proteins, such as TIR domain-containing adaptor protein (TIRAP), myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor inducing interferon-β (TRIF), and TRIF-related adapter molecule (TRAM). This assembly nucleates distinct signaling complexes that activate nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) transcription factors, leading to the production of proinflammatory cytokines and type I interferons (IFNs) (8). With the exception of TLR3 and the endosomal TLRs (TLR7/8/9), select TLRs (TLR2 and TLR4) require the bridging adaptor TIRAP to recruit MyD88, which in turn activates interleukin-1 receptor-associated kinases (IRAKs) and downstream NF-κB/Mitogen-Activated Protein Kinase (MAPK) pathways to induce proinflammatory cytokines (9). In contrast, TLR3 signals independently of MyD88 by engaging the adaptor TRIF, which activates TANK-binding kinase 1 (TBK1) and IκB kinase ϵ (IKKϵ) to phosphorylate IRF3, thereby inducing IFNs and contributing to delayed NF-κB activation (10, 11). TLR4 is unique in its ability to utilize both the MyD88-TIRAP and TRIF-TRAM axes, enabling it to orchestrate robust inflammatory responses alongside potent antiviral interferon production (12). Furthermore, endosomal TLRs, such as TLR7, TLR8, and TLR9, recognize nucleic acid ligands and can directly engage MyD88 to recruit and activate IRF7, driving rapid and robust type I interferon responses (13). Collectively, these specialized signaling architectures enable precise control of immune cell activation and effector functions, playing pivotal roles in establishing pulmonary immunity and shaping the pathogenesis of lung diseases.

TLRs are expressed in various types of immune cells, including macrophages, dendritic cells (DCs), B lymphocytes, and T lymphocytes (14). They regulate the expression of pro-inflammatory cytokines and interferons by activating key transcription factors, such as NF-κB and IRFs, thereby aiding the host in defending against a wide range of pathogenic infections and adapting to complex microenvironmental changes (15). In the lung, TLRs are predominantly expressed in immune cells such as alveolar macrophages, DCs, and lymphocytes, forming the foundation of both innate and adaptive immune responses in the respiratory system (16). Studies have shown that TLRs play critical roles in the initiation and progression of lung diseases. For instance, activation of mucosal TLR5 has been demonstrated to delay thymic involution and protect against pulmonary fibrosis through enhancement of stem cell activity (17). X-linked recessive TLR7 deficiency in males results in impaired IFN immunity and severe COVID-19 pneumonia (18). In a house dust mite-induced murine model of allergic asthma, activation of TLR3 not only enhanced the antiviral response but alleviated the viral infection via regulating immunoproteasome dysfunction (19). In addition to immune cells, TLRs are also expressed in pulmonary epithelial cells and vascular endothelial cells, which play regulatory roles in maintaining lung function (20). Therefore, TLRs are essential for defending against pulmonary infections and maintaining regional immunity balance. However, excessive activation of TLRs can lead to pulmonary inflammation and immune dysregulation, contributing to the development of pneumonia, pulmonary fibrosis, and lung cancer. It has been shown that TLR4-mediated chronic inflammatory responses lead to an imbalance in the proportions of alveolar macrophages and CD163⁺ myeloid-derived monocyte-macrophages, which represents one of the fatal mechanisms underlying COVID-19 pathogenesis (21). Air pollutants such as polystyrene microplastics can induce pulmonary inflammation and apoptosis of lung cells by activating the TLR2/NF-κB signaling pathway, ultimately leading to lung injury and fibrosis (22). Therefore, the TLR family plays a crucial role in the regulation of pulmonary inflammation and regional immunity, representing a potential therapeutic target for the intervention of lung diseases.

In this review, we aim to elucidate the regulatory roles and underlying mechanisms of TLRs in lung physiology, as well as the immunomodulatory functions of TLRs and their downstream signaling molecules in pulmonary immunity. Furthermore, we discuss how aberrant activation of TLR signaling contributes to the pathogenesis of various lung diseases, including pulmonary infectious diseases, interstitial lung diseases (ILDs), and malignancies. We also briefly summarize recent clinical studies targeting TLR pathways, highlighting their potential for therapeutic intervention. This work provides a theoretical foundation for the development of novel strategies targeting TLRs and their signaling networks in the treatment of pulmonary disorders.

2 Regulatory roles of TLRs in pulmonary physiology

2.1 TLRs in maintaining pulmonary homeostasis

As one of the first identified PRRs, TLRs play a pivotal role in the regulation of innate immunity by recognizing PAMPs and DAMPs (23). In the lung, TLRs are expressed not only in immune cells, such as alveolar macrophages and dendritic cells, but also in pulmonary epithelial cells, suggesting their critical roles in host defense against infection and normal lung development (24, 25). Using a false discovery rate algorithm, researchers have found that TLR2 was consistently upregulated across distinct stages of fetal lung development, from the early pseudo-glandular stage to the late pseudo-glandular and canalicular phases (25). In addition, the functional expression of TLR2 and TLR4 has been detected in murine pulmonary epithelial cells (26). Upon recognition of pathogen-derived molecules, these receptors promote epithelial cell proliferation (27). Studies utilizing gene knockout technology have demonstrated that Tlr2^-/- and Tlr4^-/- mice exhibit enhanced pulmonary epithelial cell apoptosis and impaired macrophage trans-epithelial migration following lung injury (28). These findings suggest that TLR2 and TLR4 play critical roles in maintaining epithelial cell integrity and facilitating tissue repair following lung injury. The protective effects of TLR2 and TLR4 on epithelial cells are predominantly mediated through the recognition of intracellular high-molecular-weight hyaluronic acid (HA) (29). As a critical mediator of tissue repair and remodeling, hyaluronic acid not only inhibits cellular apoptosis but promotes the proliferation and regeneration of surfactant protein C-positive alveolar progenitor cells through TLR4 activation, thereby inhibiting pulmonary fibrosis in mice (30, 31).

Endothelial cells are essential cells maintaining the pulmonary homeostasis through the expression of various adhesion molecules and cytokines (32). Studies have shown that Tlr2 deletion in murine pulmonary endothelial cells leads to a significant reduction in angiogenesis-associated signaling pathways, including the phosphorylation activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as the secretion of cytokine-induced neutrophil chemoattractant (CINC) (33). As a TLR2/6 agonist, macrophage-activating lipopeptide 2 kDa (MALP-2) not only promotes the proliferation and migration of endothelial cells but upregulates the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) essential for angiogenesis (34). Emerging evidence indicates that the expression of TLR3 is significantly downregulated in pulmonary endothelial cells from patients with pulmonary arterial hypertension (PAH). Knockout of Tlr3 enhances the susceptibility of endothelial cells to apoptosis in Tlr3-deficient (Tlr3^−/−) mice, thereby contributing to pulmonary vascular remodeling (35). Furthermore, the TLR3 agonist polyinosinic/polycytidylic acid [Poly(I: C)] enhances the binding of IRF3 to the bone morphogenetic protein receptor II (BMPR2) promoter, thereby inhibiting clonal proliferation of endothelial cells and alleviating pulmonary arterial hypertension (PAH) caused by vascular remodeling (36). Activation of TLR4 suppresses the expression of p16^INK4a, a senescence-associated protein, via histone deacetylase 2 (HDAC2)-mediated deacetylation of histone H4 (37). However, the silencing of Tlr4 in pulmonary endothelial cells leads to the development of emphysema. Accordingly, TLRs contribute to the maintenance of pulmonary integrity by regulating endothelial cells (Figure 1).

Figure 1

Figure 1. Roles of TLRs in pulmonary physiology and pathology. In lung physiological homeostasis, TLR4 senses intracellular HA to promote the proliferation and renewal of alveolar progenitor cells, while its activation in endothelial cells induces histone H4 deacetylation via HDAC2-mediated mechanisms, leading to the suppression of the senescence-associated gene p16INK4a and the maintenance of pulmonary integrity (30, 31, 37). The TLR2/6 agonist MALP-2 mediates ERK1/2 phosphorylation and CINC secretion upregulates GM-CSF expression and promotes pulmonary angiogenesis (34). In contrast, the TLR3 agonist Poly (I: C) suppresses endothelial cell clonogenic proliferation and attenuates vascular remodeling by enhancing IRF3 binding to the BMPR2 promoter (36). In contrast, excessive activation of TLR4 triggers Scr/VE-cadherin pathway activation and promotes alveolar macrophages and neutrophils through NF-κB hyperactivation (132). TLR2 in endothelial cells exacerbates endothelial injury and coagulation dysregulation by mediating NETs-STING interactions (130). In addition, TLR7 recognizes miR-146a-5p, leading to impaired endothelial barrier function and contributing to the development of sepsis-induced ARDS (133), while excessive TLR7/8 activation drives autoimmune vasculitis (134).

2.2 TLRs and pulmonary microbiome

The lung microbiota is closely associated with the maintenance of pulmonary homeostasis and the regulation of local alveolar immune responses, while the pulmonary immunity is crucial for the maintenance of lung Microbiome (38). In Tlr-deficient mice, the pulmonary microbiota exhibits significant dysbiosis, indicating that TLRs play a crucial role in regulating lung microbiome (39). However, selective activation of TLRs does not alter the gut microbiota in healthy mice, suggesting that under normal physiological conditions, TLR signaling has limited influence on microbial community composition (40). It has been shown that the expression of TLR9 in the lung is positively correlated with the abundance of Staphylococcus and Prevotella, and the interaction between TLR9 and the microbiota is associated with improved progression-free survival (PFS) in pulmonary fibrosis (41). These findings suggest a potential role for TLR9 in modulating the pulmonary microbiota and its impact on the pathogenesis of pulmonary fibrosis. Besides, the responsiveness of TLR4 in alveolar macrophages is reduced in individuals with a pneumotype characterized by enrichment in upper respiratory tract-associated microbiota (pneumotype SPT), and this reduction is associated with attenuated pulmonary inflammatory response (42). This difference reflects the distinct regulatory mechanisms by which different pulmonary microbiota modulate immune responses in the lung. These findings indicate that the activation of TLRs not only directly influences the composition of the pulmonary microbiota, but indirectly affects microbiota dynamics by modulating pulmonary immune and inflammatory responses.

In summary, TLRs play an indispensable role in lung development and physiological regulation. They contribute to the maintenance of normal pulmonary function through the modulation of lung epithelial and vascular endothelial cells, as well as the complicated interactions with the pulmonary microbiota. TLRs not only contribute to the maintenance of pulmonary homeostasis, but serve as key foundation linking both innate and adaptive immune defenses. Moreover, TLRs and the subsequent activation of downstream signaling pathways can trigger a range of pathophysiological changes in the lung. The functional heterogeneity of TLRs provides insight into understanding the mechanistic roles of TLRs in various pulmonary diseases.

3 Orchestrating immunity and inflammation: functions of TLR adaptors in the lung

TLRs play a pivotal role in lung development and homeostasis through recognition of specific ligands, a process reliant on highly conserved downstream signaling pathways and specialized adaptor molecules. Key adaptors, including MyD88, TIRAP, TRIF, and TRAM, form a core signaling network that not only provides a first line of defense against pathogens but also ensures immune homeostasis and prevents excessive inflammation (Table 1).

Table 1

Table 1. Functions of TLR adaptor proteins in lung immunity.

3.1 MyD88 and TIRAP

As the central adaptor for most TLRs, MyD88 recruits IRAK1 and IRAK4 via its death domain to form the Myddosome complex, activating the MAPK and NF-κB signaling pathways. This leads to the nuclear translocation of NF-κB and AP-1, rapidly inducing the pro-inflammatory cytokines such as TNF-α and IL-6, which are essential for bacterial clearance in the lung (9, 43). Within endosomes, MyD88 is recruited by TLR7, TLR8, and TLR9 to initiate the MyD88-IRF7 signaling axis, driving the phosphorylation and nuclear translocation of IRF7, resulting in robust production of IFN-α critical for antiviral immunity (13).

Studies have shown that MyD88-deficient mice exhibit significantly higher viral loads in the lungs following SARS-CoV infection (44), and display increased susceptibility and mortality during Streptococcus pneumoniae infection (45). These findings underscore the critical role of MyD88 in pulmonary host defense against both viral and bacterial pathogens. MyD88 synergizes with the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)pathway in Ly6C^hi monocytes to enhance IFN-γ production during Streptococcus pneumoniae infection (46). TIRAP facilitates MyD88 recruitment to TLR2/4 complexes (47). Similarly, Tirap-deficient mice exhibit increased mortality in bacterial lung infections. Studies have demonstrated that TIRAP is a critical mediator in the lung's defense against Klebsiella pneumoniae and Escherichia coli infections (48, 49).

However, during SARS-CoV-2 infection, aberrant activation of the MyD88/TIRAP-IRAK-NF-κB signaling axis may drive macrophage hyperactivation and cytokine storm-mediated acute lung injury (ALI) (50). Targeting this axis has emerged as a therapeutic strategy (51, 52). Interestingly, TIRAP-MyD88 inhibition promotes M2 macrophage polarization, underscoring its context-dependent role (53). MyD88 function also varies by cell type: in myeloid cells it exacerbates inflammation, whereas in stromal cells it may exert anti-inflammatory effects (54).

3.2 TRIF and TRAM

TRIF is encoded by the Ticam1 gene. The TRIF-dependent pathway, activated primarily by TLR3/4, induces IFN-β production. TRIF recruits TBK1 and IKKϵ, leading to IRF3 phosphorylation, nuclear translocation, and IFNB1 transcription. Ticam1 deficiency impairs this antiviral response (55). TRAM specifically bridges TLR4 to TRIF; its deletion disrupts TLR4-mediated TRIF-TBK1-IRF3 activation and increases viral susceptibility (55).

Beyond antiviral roles, TRIF signaling has immunomodulatory functions. The bacterial lysate OM-85 expands Tregs via dendritic cell MyD88/TRIF signaling, suppressing type 2 inflammation in asthma and promoting tolerance (56). However, in chronic inflammation such as cigarette smoke exposure, TLR4 signaling may shift from MyD88 to TRIF/caspase-8/GSDMD pyroptosis, releasing DAMPs and perpetuating tissue injury (57). Thus, MyD88 and TRIF are not simply antagonistic but form a dynamic network with bidirectional crosstalk, where outcomes depend on stimulus, cell type, and microenvironment. For instance, in ALI, TLR4 synergistically activates STING via coordinated MyD88 and TRIF signaling, amplifying inflammation (58).

Targeting TLR adaptors offers novel therapeutic potential. In experimental sepsis, TRAM deletion promotes neutrophil resolution and reprograms monocyte/macrophage function, alleviating lung injury (59). TRAM also interacts with NLRC3 in Tregs to suppress excessive inflammation and pathologic vascular remodeling (60).

Despite advances, key challenges remain. Cell type-specific functions of adaptors are incompletely defined. In chronic diseases, precise modulation, such as inhibiting detrimental MyD88-driven inflammation while preserving beneficial TRIF-mediated responses, remains a major hurdle. Studies on downstream adaptor proteins of TLRs in the lung have revealed that these adaptors are essential mediators of TLR-mediated immune defense and immunoregulation. Dysregulation of adaptor function can lead to excessive TLR activation and contribute to the development of pulmonary pathological changes. In the following sections, we will discuss the roles of TLRs in regulating both innate and adaptive immunity in the lung, as well as the mechanisms by which dysregulation of the TLR signaling network drives pulmonary disease pathogenesis.

4 Regulatory network of TLRs in pulmonary regional immunity

4.1 Regulation of innate immune responses by TLRs in the lung

The innate immune system in the lungs constitutes the first line of defense against pathogen invasion through rapid response mediated by PRRs (61). Among PRRs, TLRs initiate innate immune response upon recognition of PAMPs. Innate immune cells such as alveolar macrophages, dendritic cells, and neutrophils establish a defense network within the pulmonary microenvironment via TLRs signaling pathway (62).

4.1.1 Regulation of alveolar macrophages by TLRs

As specialized tissue-resident macrophages localized within the alveolar lumen and interstitium, alveolar macrophages play a central role in respiratory immune defense through unique tissue adaptability and phenotypic plasticity (63). Activation of TLRs is not only essential for the initiation of phagocytic function in alveolar macrophages but also facilitates the formation of immunorecognition complex through synergistic interactions with other PRRs (Figure 2) (64). It has been well demonstrated that TLR2 recognizes the influenza virus and mediates the establishment of an antiviral defense barrier in the upper respiratory tract, thereby significantly reducing the risk of viral dissemination to the pulmonary parenchyma (65). In a Mycobacterium tuberculosis (Mtb) infection model, the activation of TLR2/Radioprotective 105 kDa protein (RP105) signaling axis in alveolar macrophages promotes the expansion of the macrophage-rich region at the granuloma core (66). TLR4 forms a heterodimeric complex with the C-type lectin receptor CLEC4E, enhancing lysosome biogenesis through the phosphoinositide 3-kinase(PI3K)-STAT1 signaling pathway while simultaneously suppressing the secretion of Th2-type cytokines, such as IL-4 and IL-10, thereby enabling the clearance of Mtb (67, 68). This synergistic effect is receptor-specific. In allergic pneumonia caused by Aspergillus fumigatus, the co-activation of TLR2 and CLEC4E in bone marrow-derived dendritic cells suppresses inflammation via upregulating IL-10 in a MyD88-dependent manner (69).

Figure 2

Figure 2. Regulation of innate immune responses by TLRs in the lung. In Alveolar macrophages, the co-activation of TLR4 and CLEC4E triggers the MyD88/PtdIns3K/STAT1/NF-κB signaling pathway, enhancing lysosome biogenesis while suppressing IL-10 and IL-4 expression, thereby controlling Mtb infection (68). LPS-activated TLR4 induces a phenotypic transition from CD11blow to CD11bhigh Alveolar macrophages, modulating their response to pathogen-associated components (72). TLR7 activation in epithelial barriers promotes monocyte differentiation into AMs, reducing pulmonary viral load (74). In the tumor microenvironment, endosomal TLR7/8 activation synergizes with MR signaling to drive TAMs toward an M1 anti-tumor phenotype (82). This enhances T cell recruitment by upregulating chemokines CXCL10 and CCL5, thereby boosting anti-tumor immunity. During Aspergillus fumigatus infection, TLR2-CLEC4E co-activation in dendritic cells increases IL-10 production via MyD88, suppressing eosinophil infiltration and negatively regulating hypersensitivity pneumonitis (69). TLR5 signaling promotes dendritic cell differentiation into CD11b⁺ cDC2 subset, which then releases type I interferons through TLR3/4/7/9 activation, enhancing T cell function (86, 87). Neutrophil-expressed TLR2 recognizes lipoproteins from Prevotella species in airways, inducing TNF-α and IL-10 production (75). TLR1/2 and TLR4 activation triggers NF-κB/p65/STAT1 signaling, promoting ROS and IFN-γ release, which mediate pulmonary antibacterial immunity (91, 92).

The functional diversity of TLRs is particularly evident in bacterial pneumonia. During Streptococcus pneumoniae infection, the deficiency of endosomal TLR-mediated (TLR7/9) nucleic acid sensing pathways in alveolar macrophages leads to enhanced infection. Notably, a functional compensation between TLR7 and TLR9 in nucleic acid recognition has been observed, which plays a role in preventing S. pneumoniae from immune evasion (70). In addition, alveolar macrophages undergo phenotypic transition upon TLR activation, which affects the production of pro-inflammatory cytokines and chemokines (71). For example, in a lipopolysaccharide (LPS)-induced murine model of acute respiratory distress syndrome (ARDS), alveolar macrophages undergo a TLR4-mediated phenotypic transition from CD11b^low to CD11b^high, thereby enhancing the inflammatory response to pathogens (72). These findings confirm the central role of TLRs in the regulation of alveolar macrophages and highlight their contributions to enhanced pulmonary immune responses through synergistic interactions with other PRRs.

The immunoregulatory network of TLRs is also essential for the remodeling of tissue microenvironment. In Legionella pneumonia, infected alveolar macrophages induce an interleukin-1 (IL-1)-dependent inflammatory response, which thus stimulates alveolar epithelial cells to produce GM-CSF (73). GM-CSF signaling enhances TLR-mediated pathways in alveolar macrophages, leading to metabolic reprogramming characterized by increased glycolysis, thereby amplifying the antimicrobial activity and inflammatory cytokine production of monocytes (73). Moreover, the activation of TLR7 promotes the differentiation of pulmonary monocytes into tissue macrophages, significantly reducing pulmonary viral load (74). Neutrophil-expressed TLR2 plays a crucial role in the clearance of S. pneumoniae by recognizing lipoproteins of Prevotella species and enhancing serine protease activity (75). TLR2 agonist INNA-X activates the TLR2/NF-κB/IFN-λ signaling pathway in airway epithelial cells, thereby enhancing lymphocyte recruitment and suppressing neutrophils-mediated inflammation (76). Accordingly, TLRs help to establish a sustained innate immune response that alleviates pulmonary infections.

Alveolar macrophages exert immunosuppressive effects during the anti-tumor immune response (77). Emerging evidence indicates that TLRs enhance the efficacy of cancer immunotherapy by modulating metabolic reprogramming in alveolar macrophages (78). It has been demonstrated that HA-mannose-modified nanocapsules loaded with TLR3 agonist Poly (I: C) and TLR7/8 agonist resiquimod (R848) could specifically target alveolar macrophages in lung tumor-bearing mice (79). Activation of TLR3/7/8 induces alveolar macrophages to an CD86^highCD206^lowArg1^low M1-like antitumor phenotype, enhancing the expression of T-cell chemokines CXCL10 and CCL5 and effectively suppressing tumor metastasis (79). SHISA3 functions as a tumor-suppressive protein (80). The combination of the TLR4 agonist monophosphoryl lipid A (MPLA) and anti-PD-1 antibody promotes SHISA3 expression via the NF-κB pathway, thereby promoting antitumor M1 polarization and phagocytic capacity of alveolar macrophages (81). In addition, the TLR7/8 agonist imiquimod (IMDQ) conjugated to nanobodies regulates the mannose receptor (MR) and induces M1-like repolarization of alveolar macrophages, which obviously suppresses tumor progression (82). Taken together, these findings highlight the critical role of TLRs in regulating phenotypic transitions of alveolar macrophages during the antitumor immunity. Targeting TLRs in alveolar macrophages using agonists holds promise as a novel therapeutic strategy for pulmonary cancer.

4.1.2 TLRs regulate pulmonary dendritic cells

DCs are pivotal antigen-presenting cells in the immune system, serving as a bridge between innate and adaptive immunity (83). TLRs play a crucial role in modulating the phenotype and function of pulmonary DCs (Figure 2). For instance, TLR2 activation induces increased reactive oxygen species (ROS) production, which enhances antigen presentation and immune response in the lung (84). The TLR3 agonist Poly (I: C) activates pulmonary DCs, thereby promoting the recruitment of natural killer (NK) cells and the activation of CD8⁺ T cells (85). Besides, the TLR5 agonist flagellin promotes the expression of maturation markers such as CD40, CD80, and CD86 on lung conventional DC subsets (CD103⁺ cDC1 and CD11b⁺ cDC2), and significantly enhances their migration to mediastinal lymph nodes in neonatal mice, thereby facilitating the establishment of pulmonary mucosal immunity (86). In a murine model of respiratory infection, conventional DC type 2 (cDC2) activates TLR3/4/7/9 and downstream signaling pathways, leading to elevated type I IFNs and the inflammatory cDC2s. These inf-cDC2s exhibit a robust capacity to promote the polarization of CD4⁺Th cells toward a Th1 bias and the antigen-presenting capability to CD8⁺T cells (87).

In tumor-associated DCs, combined applications of TLR7/8 agonists and STAT3 inhibitors effectively enhance the antigen uptake and presentation by DCs, which thus promotes DC migration to lymph nodes and augments the antigen-specific cytotoxic activity of CD8⁺ T cells (88). The activation of TLR9 not only induces the expansion of tumor-associated DCs, but elicit the antitumor immune response by synergizing with PD-L1 inhibitors (89). Although studies on TLR-targeted modulation in pulmonary DCs remain limited, evidence from current research in other organs suggests that tissue-resident DCs may influence tumor development and progression by modulating the balance of the local immune microenvironment. The potential effects and mechanisms of DCs in pulmonary cancer immunity warrant further investigations in the future.

Thus, TLRs modulate the phenotype and function of DCs through distinct signaling pathways, thereby influencing T-cell activation and the magnitude of immune responses. In infection and tumor models, TLR activation significantly enhances the antigen-presenting capacity and immunomodulatory functions of DCs, providing new insight into the exploration of immunotherapy approaches in pulmonary cancer.

4.1.3 TLRs modulate lung neutrophils function

Neutrophils are critical effector cells involved in pulmonary innate immune response. Upon pathogen invasion, neutrophils rapidly migrate to the site of infection and recognize PAMPs via TLRs (90) (Figure 2). In a mouse model of S. pneumoniae-induced pneumonia, the activation of TLR1/2 and TLR4 and TANK-binding kinase 1 phosphorylation in neutrophils through the NF-κB/p65/STAT1 signaling pathway promotes the expression of ROS, IFN-γ, and IL-12p40, mediating pulmonary antibacterial immunity (91, 92). Studies have also demonstrated that activation of TLR3 and the TLR5 both enhance the early mobilization of neutrophils and pulmonary antibacterial activity (93, 94). In tumor microenvironment (TME), pulmonary neutrophils exert both antitumor and protumor effects (95). Tumor-associated neutrophils (TANs) are a critical component of the premetastatic niche (PMN) in the lung. Activation of TLR signaling pathways promotes the recruitment of TANs and their polarization toward an N2 phenotype (pro-tumorigenic), thereby accelerating lung cancer metastasis (96). In non-small cell lung cancer (NSCLC), neutrophils are activated by Annexin A2 via the TLR2-MyD88 axis, leading to increased expression of arginase 1 (97). This induction results in severe dysfunction of T cells and compromises pulmonary antitumor immune responses. However, activation of TLR7/8 in pulmonary neutrophils enhances their phagocytic capacity against tumor cells, thereby effectively inhibiting the progression of lung cancer (98). These findings highlight the potential therapeutic role of TLRs and TLRs signaling pathways in regulating neutrophils in lung cancer.

In summary, TLRs serve as the core "immune sentinels" of pulmonary innate immunity via regulating the functions of alveolar macrophages, DCs, neutrophils, and other effector cells. TLRs play vital roles in the rapid recognition and clearance of pathogens, cascading inflammatory response, and antitumor immunity in the lung, collectively maintaining pulmonary homeostasis. Most importantly, the role of TLRs extends beyond innate immunity, serving as a bridge linking innate immunity with adaptive immunity.

4.2 Regulation of adaptive immunity by TLRs in the lung

4.2.1 TLRs regulate pulmonary T lymphocytes

TLRs play a central role in pulmonary adaptive immunity by regulating T-cell functions (99). In an Mtb infection model, the absence of TLR2 signaling significantly impairs the co-stimulatory capacity of CD4⁺ and CD8⁺ T cells, resulting in decreased cytokines production, such as IFN-γ, TNF-α, and IL-10 (100). Notably, TLR2 plays a distinctive role in respiratory vaccine immune responses. Studies on SARS-CoV-2 mucosal vaccines have demonstrated that co-administration of the spike protein with TLR2 agonist Pam2Cys significantly increases the proportion of spike-specific T follicular helper cells, the capacity of CD4⁺ T cells to produce IL-17A and TNF, and the generation of anti-spike IgA and neutralizing antibody levels (101). In contrast to TLR2, intranasal subunit vaccines containing TLR3 agonists in cationic liposomes effectively induce airway IgA production and pulmonary CD4⁺ and CD8⁺ T cell responses (102). Besides, the adjuvant system incorporating the TLR3 agonist NexaVant more efficiently promotes the expansion of lung tissue-resident memory T cells via a type I IFN-dependent pathway (103). Furthermore, the combination of the MVA-SARS-2-S vaccine with a TLR3 agonist significantly increases the number of pulmonary CD8⁺ T cells (104). In contrast, the TLR9 agonist CpG primarily enhances cellular immune response by promoting pulmonary CD8⁺ cytotoxic T lymphocytes differentiation and the expression of granzyme B (105). TLR2 activation induces CD4⁺ T cells to differentiate into CD4⁺CD25⁺FOXP3⁺ Tregs, which leads to increased viral load in the Aspergillus fumigatus infection model (106). Similarly, in paracoccidioidomycosis (PCM), TLR3 facilitates fungal immune evasion by inhibiting the activation and cytotoxic function of IFN-γ⁺CD8⁺ T and IL-17⁺CD8⁺ T cells (107). The TLR2/4 signaling positively correlates with infection severity due to increased expression of suppressive factors, such as PD-L1, IL-10, and nitrotyrosine in myeloid-derived suppressor cells (MDSCs), which significantly impairs T cell antifungal activity (108). This suggests TLRs play critical roles in regulating T Lymphocytes during pulmonary infections.

The functional plasticity of pulmonary T cell responses is critically shaped by TLRs. For example, histone components within NETs induce TLR2 activation and STAT3 phosphorylation in T cells, thereby driving Th17 polarization (109). Similarly, during Mtb infection, TLR4-MyD88 signaling orchestrates DC maturation and cytokine production, notably IL-12p70 and IL-23p19, via T-bet upregulation. This process facilitates the differentiation of CD4⁺ T cells into Th1 and Th17 subsets, which are critical for effective antimicrobial immunity (110). Interestingly, TLR4 agonist glucopyranosyl lipid adjuvant suppresses the differentiation of pulmonary CD8⁺ T cells by limiting T cell receptor signaling, thereby promoting respiratory mucosal immunity via upregulating memory T cell formation and TH17/TC17 responses (111). In contrast, TLR9 agonist CpG promote TH1/TC1 effector cells expansion but inhibiting TH17 differentiation (111). In NSCLC, TLR3/TLR7 agonists effectively counteract TGF-β-mediated immunosuppression by inducing IFN-γ production, thereby inhibiting Treg expansion (112). Activation of NF-κB and IRF3 signaling pathways enhances CD8⁺ T cell functions, promoting antitumor immunity. Additionally, in lung adenocarcinoma models, the efficacy of antitumor drugs is closely related to the cytotoxic function of CD8⁺ T cells mediated by TLR4 (113). Treatment with a TLR9 agonist in combination with TGF-β2 inhibitor enhances the antitumor activity of CD8⁺ T cells (114). Accordingly, TLRs are essential for T cells-mediated tumor immunity in the lung. All these findings highlight the complex regulatory networks of TLRs in pulmonary adaptive immunity. Nonetheless, the specific mechanisms by which TLRs regulate T lymphocytes in the lungs still require further investigations in future studies.

4.2.2 Regulation of pulmonary B lymphocytes by TLRs

TLRs regulate B cell-mediated humoral immunity in the lungs through both B cell-intrinsic signaling and microenvironment-dependent pathways. TLR4 collaborates with B cell receptor via the TLR4-TRIF pathway to induce the production of the monocyte chemoattractant CCL7, a molecule critical for initiating neutrophil extravasation and monocyte recruitment in the lungs (115). In a Brucella infection model, pulmonary B cell TLR2/4 is essential for the early IgG production, while downstream MYD88 activation is associated with the production of antigen-specific IgG in the later stages (116). In antiviral immunity, the TLR7-IRF7-IFNα/γ axis directly affects the efficiency of antiviral antibody production by B cells. Double-knockout of both Tlr7 and Irf7 leads to reduced IFN-α and IFN-γ, impaired antibody production, and delayed viral clearance in the lungs (117). Notably, the combination of TLR7 agonist imiquimod with inactivated viral particles can directly induce naïve B cells to differentiate into plasma cells, highlighting the critical role of TLR signaling in B cells response (118). Moreover, the maintenance of glycolytic metabolic activity and mitochondrial homeostasis in B cells depends on TLR9 signaling and the co-stimulation by helper T cells (119). This regulatory mechanism not only enhances the anti-apoptotic capacity of B cells, but promotes their differentiation into effector B cells. Notably, in the context of autoimmune pathology, abnormal activation of B cells by TLRs can lead to pathological responses. For instance, small nuclear RNAs can activate B cell TLR7, driving the production of anti-dsDNA and anti-Smith antibodies in SLE (120). In patients with systemic sclerosis (SSc), the intrinsic hyperactivation of TLR9 in B cells contributes to immune dysregulation (121). Aberrant activation of TLR9 in regulatory B cells (Bregs) further disrupts the function of the STAT3 and p38 MAPK signaling pathways, leading to a reduction in Breg and abnormal upregulation of CD19 (122). In a mouse model of SSc, CD19 deficiency has been shown to significantly attenuate lung fibrosis and autoantibody production in response to TLR4 activation (123). Accordingly, targeting TLRs pathway may represent a novel therapeutic strategy for autoimmune-mediated lung injury.

It has been well documented that the activation of TLR3 in lung epithelial cells leads to the release of B cell activating factor, which effectively promotes the survival of memory B cells and plasma cell differentiation (124). In contrast, excessive activation of TLR9 exerts anti-inflammatory effects in the lung by inducing Bregs to secrete IL-10 (125). Besides, the TLR7/9 signaling pathway has been shown to play a unique role in adaptive immune response by driving the IgD⁺CD21^-CD23^- age-associated B cells (ABCs) differentiation into infection-induced ABCs and memory B cells, which are crucial for defending against influenza A virus infection among elderly individuals (126). Moreover, in a schistosome infection model, reduced response of lung B cells to TLR4/9 stimulation leads to decreased IL-10 and increased CD86 expressions, which alleviates allergic airway inflammation by suppressing Th2 polarization (127). These findings have highlighted the environment-dependent functional plasticity of TLRs in regulating pulmonary adaptive immunity.

In summary, TLRs play important roles in the regulation of pulmonary adaptive immunity. They contribute to the activation and recruitment of immune cells to establish an effective defense network against pathogens. In pathological states, aberrant TLRs activation causes excessive inflammatory response, chronic inflammation, tumor immune evasion, and autoimmune disorders. This functional plasticity of TLRs underscores the promising use of TLRs-targeted immunotherapeutic strategies for pulmonary diseases by controlling TLRs-mediated innate and adaptive immune responses.

5 Dysregulation of TLR networks in pulmonary pathologies

TLRs play essential roles in maintaining pulmonary homeostasis and immune and immune defense; however, their aberrant activation is implicated in various lung pathophysiological processes (Figure 1). Endothelial injury and interstitial fibrosis, common features in pulmonary disorders, are closely linked to dysregulated TLR signaling (128, 129). For instance, endothelial TLR2 facilitates cell injury and coagulopathy by mediating neutrophil extracellular trap (NET)-STING interactions (130). In LPS-induced ARDS, the SP1-TLR2-NF-κB axis downregulates versican V1 in lung fibroblasts, amplifying inflammation (131). TLR4 activation by LPS disrupts endothelial barrier integrity via Src/VE-cadherin signaling (132). Beyond bacterial ligands, TLR7 recognizes extracellular miR-146a-5p and aggravates pulmonary endothelial dysfunction in sepsis-associated ARDS (133). Additionally, TLR7/8 activation promotes endothelial injury and fibrosis, contributing to autoimmune vasculopathy (134).

TLR signaling is further influenced by gut microbiota dysbiosis. Postnatal growth restriction in extremely preterm infants predisposes to bronchopulmonary dysplasia and pulmonary hypertension, linked to microbiota-driven TLR4 activation in the lung (135). Moreover, LPS-induced TLR4 signaling desensitizes alveolar macrophages, impairing immune defense and promoting lung structural abnormalities (136).

This section examines the pathological outcomes of dysregulated TLR activation across pulmonary diseases, including infectious, allergic, inflammatory, and malignant conditions such as asthma, COPD, ILD, and lung cancer. The analysis aims to elucidate underlying molecular mechanisms and inform TLR-targeted therapeutic strategies.

5.1 TLRs in pulmonary infectious diseases

5.1.1 TLRs in bacterial pneumonia

Infectious pneumonia poses a significant global public health challenge, with the pathogenesis intricately linked to TLR-mediated inflammatory cascades. TLRs exhibit complex molecular regulatory mechanisms that balance host defense and immunopathology (137–139). In bacterial pneumonia, the TLR family is essential for pathogen-specific recognition (Table 2). TLR2 recognizes peptidoglycan (PGN) and lipoproteins derived from Gram-positive bacteria, driving IL-8 secretion and neutrophil recruitment in a S. pneumoniae infection (140). This process is essential for pathogen clearance; however, excessive activation of TLR2 leads to acute lung injury. Notably, Acinetobacter baumannii activates the TLR2/NF-κB/IQGAP1 pathway via its outer membrane protein A, leading to the redistribution of E-cadherin in lung epithelial cells and the epithelial barrier dysfunction (141). As a result, TLR2 plays dual roles in maintaining the epithelial barrier integrity. TLR4, as the core receptor for LPS from Gram-negative bacteria, mediates inflammatory storm through activation of the MyD88/NF-κB-dependent signaling pathway (142, 143). Pathogen-induced activation of TLR4 often triggers excessive activation of NF-κB and the subsequent production of inflammatory cytokines, leading to infiltration of alveolar macrophages and neutrophils and ultimately pulmonary injury (144). In a Staphylococcus aureus pneumonia model, the interaction between aconitate decarboxylase 1 (ACOD1) and TLR4 exacerbates lung injury by activating NF-κB signaling (145). Natural compounds such as Anemoside B4 mitigate lung injury via the TLR4/MyD88 pathway (146), whereas TLR4 activation by monophosphoryl lipid A (MPLA) can synergize with antibiotics to enhance bactericidal effects (147). Additionally, other TLR-dependent therapeutic strategies are particularly noteworthy. For instance, mesenchymal stem cell-derived microvesicles (MVs) enhance the antimicrobial activity of human alveolar macrophages through TLR3 pre-activation, thereby improving the efficacy of MVs (148). TLR5 agonist flagellin exhibits broad-spectrum anti-inflammatory effects in a dual infection model of Pseudomonas aeruginosa and S. pneumoniae by inhibiting NF-κB nuclear translocation (149, 150). In a Pseudomonas aeruginosa infection model, the absence of TLR7 not only enhances IL-10-mediated anti-inflammatory responses, but significantly promotes bacterial clearance (151). This suggests the vital role of TLR7 in infectious pneumonia caused by Gram-negative bacteria. TLR9 specifically recognizes CpG DNA from Prevotella and other pathogens, which suppresses neutrophil phagocytic activity and facilitates bacterial escape from host defenses by promoting elastase release and downregulating complement C5a (152). Notably, nanoscale outer membrane vesicles secreted by Gram-negative bacteria activate lung macrophages via the TLR4-TRIF pathway (153).

Table 2

Table 2. Effects of mechanisms of TLRs in immune regulation of different pulmonary diseases.

5.1.2 TLRs in viral pneumonia

The TLR regulatory network in viral pneumonia exhibits greater complexity (Table 2). The binding of the SARS-CoV-2 spike protein to TLR4 not only enhances angiotensin-converting enzyme 2 (ACE2) expression and disrupts type II alveolar cells, but induces M1 polarization via endothelial cell-derived secreted protein acidic and rich in cysteine-like 1 (SPARCL1) (154). Moreover, TLR4 can be modulated by extracellular vesicles (EVs)-derived miRNAs in COVID-19. In the early stage, EVs-delivering miR-146a-5p suppresses TLR4 activation to limit excessive inflammatory response. In the later stage, EVs-delivering let-7e-5p leads to more severe pulmonary inflammation and tissue damage by upregulating TLR4 expression, thereby inducing ARDS during COVID-19 infection (155). Furthermore, studies on respiratory syncytial virus and influenza virus further elucidate the dual roles of TLRs. TLR3 activation can induce an antiviral response in lung epithelial cells by promoting the expression of IFN-λ (156). However, excessive TLR3 activation can lead to epithelial barrier damage. Although TLR7-mediated IFN/ISG antiviral responses inhibit SARS-CoV-2 replication (157), they exacerbate pulmonary dysfunction in influenza A virus infection (158). Similarly, TLR9-mediated clearance of influenza virus occurs alongside tissue damage (159), suggesting that precise regulation of TLRs signal may be key to overcoming the therapeutic bottleneck in infectious pneumonia.

Current evidence has supported that the bidirectional regulation strategy of immune activation and anti-inflammation with TLR-targeted drugs exhibits unique therapeutic potential in virus-associated infectious pneumonia. The synergistic application of TLR2/6/9 agonists Pam2 CSK4 (Pam2) and CpG oligodeoxynucleotides (ODN) enhances the recruitment of pulmonary phagocytes and the cytotoxicity of natural killer cells (160). Flavonoid glycosides achieve the blockade of influenza A virus (IAV) infection by inhibiting the expression of TLR3/4/7 and the phosphorylation of NF-κB/p65 in the lung tissues of acute lung injury (ALI) mice (161). These findings indicate that TLR-targeting drugs may offer new approaches for complex viral infections.

5.1.3 TLRs in fungal and mycoplasmal pneumonia

TLRs signaling also plays essential role in regulating Fungal and mycoplasma-associated infectious pneumonia (Table 2). Cryptococcus neoformans promotes the conversion of macrophages towards an IL-4-sensitive phenotype utilizing a virulence factor (CPL1) through the TLR4/STAT3 axis (162). Mycoplasma pneumonia is demonstrated to induce a sustained low-grade inflammatory response, characterized by upregulated TNF-α and IL-1β expression in macrophages by activating TLR4 and forming an autophagy-NF-κB positive feedback loop (163). TLR4-induced persistent inflammation drives the progression of chronic inflammatory diseases. Besides, elevated TLR2 expression in the peripheral blood of children with Mycoplasma pneumoniae pneumonia is positively correlated with neutrophil infiltration (164).

As evidenced above, TLRs play complicated roles in infectious pneumonia, which are involved in the initiation of host defense by the recognition of PAMPs, the inflammatory storms, and pulmonary tissue damages in infectious pneumonia due to abundant activation of TLRs signaling pathways. Targeting TLRs and the downstream signaling pathways holds great promise for the treatment of infectious pneumonia.

5.2 TLRs in non-infectious pulmonary diseases

5.2.1 Asthma and COPD

Asthma and COPD are both classified as chronic airway inflammatory disorders, primarily characterized by inflammatory cell infiltration and the release of pro-inflammatory mediators. Clinically, patients exhibit not only significant airflow limitation but also varying degrees of airway hyperresponsiveness (165, 166). Emerging studies have demonstrated that TLRs play a pivotal role in modulating chronic airway inflammatory disorders through the crosstalk between innate and adaptive immunity (167, 168) (Table 2).

A previous study suggests that excessive activation of TLR2/4/7 drove airway inflammation in COPD by enhancing the nuclear export of TLR2 mediated by exportin XPO6 in monocytes, which leads to increased production of TNF-α and IL-6 through the activation of TLR2/MyD88/NF-κB pathway (169). TLR2 promotes Th2 cell polarization in asthma by thymic stromal lymphopoietin (TSLP)-mediated NF-κB and JNK signaling pathways activation in the airway epithelial cells (170). Air pollution material (PM) causes airway inflammatory disorders by inducing increased production of IL-6 and CXCL1/2 in airway epithelial cells through the TLR4/MyD88 and mTOR-autophagy signaling pathways (171). Additionally, cigarette smoke activates mast cell degranulation via TLR7, promoting the release of mast cell protease-6 (MMCP-6) and exacerbating emphysema in COPD (172). However, the TLR7 agonist R848 leads to the dysregulation of the innate immune response in nasal mucosa through the upregulation of IFN-α2a, CCL3, and CCL13 in asthma patients (173). Notably, TLR3 activation promotes high expression of IL-13 in type 2 innate lymphoid cells (ILC2) and alveolar macrophages, leading to airway hyperresponsiveness and increased mucus production (174). However, during the chronic phase, stimulation with the TLR3 agonist poly (I: C) inhibits ILC2 differentiation through the IFN-β/STAT5/GATA3 pathway, thereby suppressing type 2 immune response in the lung (175). In COPD, NET-derived DNA promotes NF-κB-dependent autoimmunity via the cGAS/TLR9 pathway, contributing to persistent airway inflammation (176). Nonetheless, TLR9 agonists have been shown to inhibit eosinophil infiltration in asthma due to the expansion of Bregs (177). Additionally, activation of TLR5 has been found to exacerbate airway inflammation in asthma (178, 179), whereas the regulatory DCs (rDCs) and Tregs can suppress TH1/TH2/TH17 responses in a TLR5-dependent manner, thereby inhibiting the development of experimental asthma (180). These findings have implicated the complicated roles of TLRs in the regulation of chronic inflammatory lung diseases, underscoring the significant challenge of achieving precise immune modulation using TLR-based therapies in the future.

5.2.2 ILDs

ILDs comprise a heterogeneous group of pulmonary disorders characterized by interstitial inflammation and fibrosis, often leading to progressive dyspnea and end-stage respiratory failure. Idiopathic Pulmonary Fibrosis (IPF) is the most prevalent subtype, accounting for approximately one-third of ILD cases. Additionally, Connective Tissue Disease-associated Interstitial Lung Disease (CTD-ILD) and hypersensitivity pneumonitis (HP) are common subtypes, representing 25% and 15% of cases, respectively (181). This section focuses on elucidating the mechanisms by which TLRs drive disease initiation and progression in major ILD subtypes, including IPF, CTD-ILD, hypersensitivity pneumonitis, and silicosis.

5.2.2.1 IPF

IPF is a chronic progressive ILD with unknown etiology, pathologically defined by aberrant fibroblast activation, alveolar epithelial cell dysfunction, and macrophage-driven inflammation (182). Accumulating evidence demonstrates that dysregulated TLR signaling contributes centrally to IPF pathogenesis through orchestrating inflammatory cascades, metabolic reprogramming, and fibrotic remodeling (Table 2).

The genetic polymorphisms of TLR3 (specifically the L412F variant) are linked to accelerated disease progression and higher mortality in IPF, underscoring the role of TLRs in phenotypic modulation (183). Fibroblast-expressed TLR9 recognizes circulating mitochondrial DNA (mtDNA) and acts synergistically with transforming growth factor-beta 1 (TGF-β1) to promote fibroblast activation, triggering the release of pro-inflammatory mediators, such as MCP-1 and IL-6 (184). This establishes a pro-fibrotic feedback loop culminating in excessive extracellular matrix (ECM) deposition (184). TLR9 also upregulates TDO2 in fibroblasts, increasing kynurenine production, which activates the AHR pathway in CD103⁺ dendritic cells and enhances IL-6-driven inflammation and fibrosis (185). Additionally, epithelial TLR9 engages the NLRP3 inflammasome to promote caspase-1-mediated pyroptosis, further contributing to IPF pathogenesis (186). These findings collectively underscore the critical role of TLR9 in the regulation of pulmonary fibrosis.

Host-microbe interactions also promote fibrotic in IPF via TLR2/4. Dysbiosis-associated outer membrane vesicles (OMVs), particularly derived from Bacteroides and Prevotella species, activate AMs via the TLR2/4-MyD88 signaling axis, thereby inducing a profibrotic network involving IL-17B and TNF-α (187). This upregulates neutrophil chemokines (e.g., G-CSF, CXCL1, CXCL2) and Th17 differentiation genes (e.g., IL-6, Saa1/2), fostering neutrophil infiltration and Th17 responses that accelerate fibrosis (187). Unlike classical autoimmune ILDs, IPF appears driven primarily by DAMPs and microbiota-derived ligands rather than autoantibody-mediated TLR activation.

In addition, the TLR4 signaling pathway plays multiple roles in IPF. Activation of the TLR4-MyD88-NF-κB axis in AMs leads to aberrant AM proliferation and disruption of the "autophagy-apoptosis" equilibrium, significantly exacerbating disease progression (188). Elevated eNAMPT-a DAMP and TLR4 ligand—in IPF patients correlates with severity and drives alveolar type II cell proliferation and EMT via TLR4, facilitating pathological remodeling (189). TLR4 also interacts with THBS1 to induce M2 macrophage polarization and glycolytic activation, establishing a pro-fibrotic microenvironment (190).

In summary, TLRs integrate signals from microorganisms, DAMPs, and cellular stress through key pathways, including MyD88, NF-κB, NLRP3, and metabolic reprogramming, forming a central bridge between innate immunity, chronic inflammation, and fibrosis in IPF. Targeted inhibition of specific TLRs or downstream effectors may offer promising therapeutic strategies for IPF.

5.2.2.2 CTD-ILD

CTD-ILD is a significant complication of systemic autoimmune disorders, such as rheumatoid arthritis, systemic sclerosis, and dermatomyositis. The pathogenesis of CTD-ILD is closely linked to dysfunction of alveolar type II epithelial cells (AEC II), inflammatory cascade activation, and aberrant fibroblast activation (191). TLRs play a crucial role in immune activation and fibrosis progression of CTD-ILD by recognizing DAMPs or PAMPs (Table 2).

TLR family is dysregulated in lung tissues of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) (129). Extracellular vesicle-delivered mtDNA can activate the cGAS/STING pathway via TLR9, promoting the secretion of type I IFNs and IL-6, thereby driving the accumulation of α-smooth muscle actin (α-SMA)⁺ myofibroblasts (192). TLR8 is significantly upregulated in monocytes during the early stage of SSc-ILD (193). However, declined expression of TLR8 is well demonstrated in the late stages of the of SSc-ILD (129). In addition, TLR/CXCL4 signaling exacerbates endothelial cell activation and fibrosis by inhibiting the transcription factor FLI1 (194). As a small-molecule inhibitor of TLR4, TAK242 can suppress collagen synthesis in fibroblasts, offering a potential therapeutic strategy for SSc-ILD (195). The anti-melanoma differentiation-associated gene 5 (MDA5) antibody is positively associated with amyopathic dermatomyositis-associated interstitial lung disease (CADM-ILD) (196, 197). Overactivation of the TLR7/9-IRF7 axis leads to aberrant production of IFN-α, while MDA5 autoantibodies promote IL-6 secretion by activating CD4⁺ T cells via TLR3 (197, 198). The therapeutic efficacy of anti-CD4 antibodies and IL-6 receptor antagonists further validates the critical role of TLR7/9-IRF7 axis (197). Additionally, the interaction between carbamylated TLR5 on AEC II cells and anti-carbamylated protein (anti-CarP) antibodies can induce nuclear translocation of NF-κB and promote EMT in AEC II, thereby accelerating fibrosis (199). Systemic lupus erythematosus (SLE) is characterized by significant mitochondrial dysfunction, where mitochondrial damage releases mtRNA that can be recognized by TLR7, subsequently triggering type I IFN responses (200–202). Notably, TLR7/8 can participate in the vascular remodeling abnormalities seen in autoimmune diseases by regulating the Th17/Treg balance, a process that is associated with complications such as pulmonary arterial hypertension (134). Additionally, TLR4-mediated autophagy and NET formation have been linked to diffuse alveolar hemorrhage in SLE (203). Therefore, TLRs play a crucial role in the regulation of CTD-ILD, serving as potential targets for disease treatment.

In summary, TLRs play a crucial role in the development and progression of CTD-ILD by regulating fibroblast activation, inflammatory cytokine release, and autoantibody production. These findings not only highlight the central role of TLRs in CTD-ILD, but provide new insights into the mechanisms of autoimmune diseases and the explanation of targeted therapies.

5.2.2.3 HP and Other ILDs

The pathogenesis and progression of HP and other ILDs are closely associated with immune and inflammatory responses mediated by TLR signaling. Although the mechanisms vary considerably across different etiologies and experimental models, certain common pathways have emerged (Table 2).

In a model of HP induced by Saccharopolyspora rectivirgula antigen, activation of the TLR2-NF-κB signaling pathway promotes the expansion of matrix metalloproteinase-14 (MMP14) high expressed macrophage subset and the release of exosomes (204). This subset enhances fibroblast-to-myofibroblast transition (FMT), thereby exacerbating pulmonary fibrosis (204). In contrast, in mycobacterium-induced HP, the activation of CD11b⁺CD11c⁺ dendritic cells via the TLR9-MyD88 pathway serves as a key mechanism in the development of lung inflammation. This process occurs independent of pathogen infectivity, highlighting the specific role of TLR9 in non-infectious immune responses (205).

In a silica (SiO₂)-induced model of silicosis, SiO₂ particles activate the TLR4-NF-κB/MAPK signaling pathway in macrophages, leading to macrophage pyroptosis and fibroblasts and alveolar epithelial cells activation, significantly amplifying pulmonary inflammation and fibrosis (206). Galectin-3 (Gal3) derived from senescent endothelial cells simultaneously engages TGFBR1 on fibroblasts and TLR4 on macrophages, thereby mediating endothelial-mesenchymal and endothelial-immune crosstalk (206). This interaction synergistically promotes both FMT and NLRP3 inflammasome activation, contributing to the progression of interstitial lung pathology (206). Moreover, dysbiosis of the lung microbiota resulting from LPS/TLR4 activation has also been found to promote the progression of silica-induced fibrosis (207), underscoring the key role of microbe-host interactions in environmentally-related lung diseases.

In summary, TLR-mediated activation of downstream cascades, including NF-κB, MAPK, and MyD88, orchestrates multicellular crosstalk among macrophages, dendritic cells, fibroblasts, and endothelial cells in both hypersensitivity pneumonitis and silicosis, thereby driving coordinated inflammatory and fibrotic responses. These insights not only underscore the centrality of TLR signaling networks in the pathogenesis of interstitial lung diseases but also highlight the therapeutic potential of targeting specific TLRs or their effector pathways to attenuate fibrosis progression.

5.2.3 Lung carcinomas

TLRs exert complex effects on the initiation, progression, and immune microenvironment of lung cancer. TLR2 enhances lung cancer cell migration and invasion by promoting the expression of CCL2, IL-6, and MMP-2 through the cAMP-AMPK-TAK1 signaling axis (208). Nonetheless, TLR2 also exhibits anti-cancer effects under specific conditions. In NSCLC, TLR2 activation induces tumor cell senescence by activating the p53-p21 pathway and promoting the expression of pro-inflammatory senescence-associated secretory phenotype (SASP) (209). Besides, TLR3 contributes to the establishment of a pro-tumorigenic inflammatory microenvironment to promote lung cancer progression via NLRP3 inflammasome activation and subsequent IL-1β release (210). Autophagy promotes tumor cell survival and migration (211). Accumulated studies have suggested TLRs are involved in the regulation of autophagy and the pre-metastatic niche (212, 213). TLR4 can enhance tumor survival and metastasis by inducing autophagy via the TRAF6-BECN1 axis (214). TLR3/4 activation results in the upregulation of chemokines CCL2/MCP-1 and immunosuppressive factors VEGFA and MMP2, which collectively promotes lung cancer invasion and metastasis through the adaptor protein TICAM1/TRIF and the activation of downstream MAPK/NF-κB signaling pathway (215). Nontypeable Haemophilus influenzae (NTHi) induces lung epithelial cells to secrete IL-17C via TLR2/4 signaling, thereby promoting lung cancer progression (216). Moreover, microbial metabolites, such as FFAR, can inhibit lung cancer progression through functional competition with TLR2/4 (208). Additionally, the activation of endogenous TLR7 within tumors can recruit MDSCs, which facilitates EMT and the metastasis of lung adenocarcinoma (217). It has been demonstrated that mitophagy-released mtDNAs activate cancer stem-like cells (CSCs) via the TLR9-Notch1-AMPK axis, leading to chemoresistance and tumor recurrence (218). These findings indicate that TLR signaling play critical roles in tumorigenesis, metastasis, cancer resistance to therapy and microbial interaction in lung carcinomas (Table 2).

The pre-metastatic niche is a microenvironment created by the primary tumor in secondary organs and tissues that facilitates subsequent metastasis (219). TLRs are also involved in lung cancer metastasis by regulating the pre-metastatic niche. In metastatic lung cancer, TLR4 in alveolar macrophages promotes pulmonary metastasis by recruiting monocyte-derived myeloid-derived suppressor cells (mo-MDSCs) and activating the CXCL10-CXCR3/CCL12 axis (220). Heat shock protein 70 (HSP70) recruits polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) through the TLR4-Wnt5a-CXCL5/G-CSF axis, contributing to the establishment of a pre-metastatic niche and resistance to immunotherapy in lung cancer (221). Additionally, the tumor-derived exosomal RNAs promote lung pre-metastatic niche formation via activating TLR3, driving neutrophil infiltration and the establishment of a pre-metastatic microenvironment (222). Accordingly, targeting TLRs and TLR signaling may represent a novel immunotherapeutic strategy in lung cancer.

6 Overview of clinical studies on TLRs- and TLRs signaling-based drugs

In recent years, significant advance has been made in therapeutic drugs targeting TLRs and the TLRs signaling pathways, which holds promising therapeutic potentials in lung cancer, asthma, and COPD (Table 3) (223).

Table 3

Table 3. Overview of clinical studies on TLRs and TLR signaling pathways.

6.1 TLR agonists

In clinical trials, the TLR9 agonist IMO-2055 in combination with erlotinib and bevacizumab (no. NCT00633529), as well as DV281 combined with nivolumab (no. NCT03326752), demonstrates favorable tolerability and enhanced antitumor immune response in patients with advanced NSCLC (224, 225). As TLR9 agonist, CpG ODN (K3) prolongs the survival of lung cancer patients by inducing IFN-α secretion and the expansion of T-bet⁺ CD8⁺ T cells (no. UMIN-000023276) (226). However, targeted TLR activation aimed at enhancing antitumor or anti-pathogen immunity inherently may inadvertently aggravate pre-existing inflammatory conditions. For example, the TLR9 agonist PF-3512676 in combination with chemotherapy regimens (paclitaxel/carboplatin or gemcitabine/cisplatin) showed limited efficacy in improving overall survival in lung cancer patients, accompanied by risks of immune exhaustion, highlighting the hazards of excessive or non-specific TLR activation (no. NCT00254891) (227, 228).

TLR2/4 agonists exhibit unique value in reshaping the immune microenvironment. Bacillus Calmette-Guérin-cell wall skeleton (BCG-CWS) leads to tumor regression in lung cancer patients by inducing the secretion of IL-12 and IL-18 via the TLR2/4-macrophage (Mφ)/antigen-presenting cell (APC) axis (229). Besides, the TLR-2 agonist CADI-05 activates an anti-angiogenic phenotype in TANs from patients with squamous cell lung carcinoma (no. NTC00680940) (230). However, the efficacy of TLR agonists is significantly influenced by diverse factors. In smokers and COPD patients, the expression of TLR2 in alveolar macrophage is significantly reduced (231). Nicotine restores TLR2/9 responsiveness by upregulating CD4⁺CD25⁺FoxP3⁺ Tregs (no. NCT00701207) (232). This variability underscores the risk of failure inherent in sole reliance on TLR-targeted agonist therapies and highlights their potential unsafety in non-responsive patient subpopulations. The central challenge for future research lies in precisely identifying patient cohorts who benefit from TLR modulation, defining the therapeutic window, and advancing biomarker-driven personalized therapy to balance efficacy and safety. Furthermore, the antiviral immune model established by the TLR7/8 agonist R848 in the respiratory mucosa offers new perspectives for combined interventions targeting virus-associated lung tumors (no. NCT02090374) (233).

6.2 TLR inhibitors and TLRs signaling-targeted drugs

Significant progress has been made in the development of TLRs inhibitors. The TLR3 monoclonal antibody CNTO3157 reduces rhinovirus-induced airway hyperresponsiveness in healthy subjects; however, it shows limited efficacy in improving symptoms in patients with COPD (no. NCT01704040) (234). In asthma, TNFAIP3 (A20) mimetic peptides reduce the frequency of acute exacerbations in asthmatic children from urban areas by inhibiting the TLR4/TRAF6/NF-κB pathway (235). These findings suggest that targeting TLRs and TLR signaling could be an effective method to manage asthma symptoms and improve the quality of life in affected populations. Thus, TLR-targeted therapies are promising in the treatment of pulmonary diseases. A thorough understanding of the regulatory immune networks governing TLRs and TLR signaling may provide novel insight into the exploration of precision medicine strategies in pulmonary diseases. Chronic pulmonary diseases, such as COPD and asthma, involve persistent inflammation and immune dysregulation. In such settings, TLR agonists risk amplifying pathological inflammation, potentially leading to adverse events and clinical worsening. Conversely, TLR antagonists may systemically inhibit essential TLR pathways, compromising anti-infective immunity and increasing susceptibility to opportunistic infections—particularly in immunocompromised individuals, including those with cancer or chronic respiratory conditions.

7 Conclusions and future directions

TLRs are essential for the maintenance of lung homeostasis by regulating epithelial barrier integrity, endothelial cell activity, microbial communities balance and immune cells functions. The well-established immune network by TLRs and TLR signaling pathways plays a pivotal role in pathogen clearance and the initiation of adaptive immunity. However, the recognition of PAMPs/DAMPs by TLRs function as a double-edged sword. Excessive activation of TLRs signaling can disrupt the immune balance, leading to pathogen escape, abundant inflammation, tissue damage, and malignant transformation. Currently, there are increasing clinical studies investigating the efficacy of TLRs- and TLRs signaling-based therapies in pulmonary diseases, including agonists and inhibitors. Most importantly, the functions and roles of TLRs in lung immunity remain not fully understood. It is of great importance to elucidate the involvement of TLRs and TLR signaling network in the onset and progression of lung diseases, including infections, fibrosis, malignancies, and immune disorders. More future clinical studies are warranted to explore the optimized therapeutic strategies targeting TLRs and TLR signaling in pulmonary diseases.

Author contributions

ZQ: Writing – original draft. ZG: Writing – original draft. YC: Writing – original draft. XG: Writing – original draft. MC: Writing – review & editing. PW: Writing – review & editing. DX: Writing – review & editing.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This work is supported by funds from the National Natural Science Foundation, China (82171790) and Weifang City Science and Technology Development Plan, Weifang, Shandong Province, China (2022YX097 and 2023YX092 and 2024YX006).

Acknowledgments

The figures in this review are created with BioRender.com.

Conflict of interest

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

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Glossary

PRRs: pattern recognition receptors

PAMPs: pathogen-associated molecular patterns

DAMPs: danger-associated molecular patterns

IRFs: interferon regulatory factors

TM: transmembrane

TIRAP TIR: domain-containing adaptor protein

LRRs: leucine-rich repeats

MD2: myeloid differentiation factor 2

dsRNA: double-stranded RNA

MyD88: myeloid differentiation factor 88

IRAK4: interleukin-1 receptor-associated kinase 4

RIP1: receptor-interacting protein 1

TRADD: TNFR-associated death domain protein

ERK1/2: extracellular signal-regulated kinases 1 and 2

CINC: cytokine-induced neutrophil chemoattractant

MALP-2: macrophage-activating lipopeptide 2 kDa

GM-CSF: granulocyte-macrophage colony-stimulating factor

PAH: pulmonary arterial hypertension

BMPR2: bone morphogenetic protein receptor II

PAH: pulmonary arterial hypertension

NETs: neutrophil extracellular traps

ARDS: acute respiratory distress syndrome

PFS: progression-free survival

RP105: Radioprotective 105 kDa protein

PI3K: phosphoinositide 3-kinas

Mtb: Mycobacterium tuberculosis

MPLA: monophosphoryl lipid A

ROS: reactive oxygen species

NK: natural killer

TME: tumor microenvironment

TANs: Tumor-associated neutrophils

NSCLC: non-small cell lung cancer

MDSCs: myeloid-derived suppressor cells

Tregs: regulatory T cells

SSc: systemic sclerosis

Bregs: regulatory B cells

CADM: Clinically Amyopathic Dermatomyositis

SLE: Systemic Lupus, Erythematosus

CTD-ILD: Connective Tissue Disease-Associated Interstitial Lung Disease

SPARCL1: Secreted Protein Acidic and Rich in Cysteine-Like 1

ACOD1: Aconitate Decarboxylase 1

CPL1: Cell Wall Protein 1

STAT3: Signal Transducer and Activator of Transcription 3

mtDNA/RNA: Mitochondrial DNA/RNA

CpG DNA: Cytosine-phosphate-Guanine DNA

NE: Neutrophil Elastase

XPO6: Exportin 6

mTOR: Mechanistic Target of Rapamycin

CCL3/13: C-C Motif Chemokine Ligand 3/13

CXCL1/2: C-X-C Motif Chemokine Ligand 1/2

CXCR3 C-X-C: Motif Chemokine Receptor 3

cGAS: Cyclic GMP-AMP Synthase

JNK: c-Jun N-terminal Kinase

TSLP: Thymic Stromal Lymphopoietin

moDC: Monocyte-Derived Dendritic Cell

GATA3: GATA Binding Protein 3

rDCs: Regulatory Dendritic Cells

TH1/TH2/TH17: T Helper 1/2/17 Cel

Breg: Regulatory B Cell

α-SMA: Alpha-Smooth Muscle Actin

MDA5: Melanoma Differentiation-Associated Protein 5

Anti Carp: Anti-Citrullinated Protein Antibody

EMT: Epithelial-Mesenchymal Transition

Notch1: Neurogenic Locus Notch Homolog Protein 1

CSC: Cancer Stem Cell

G-CSF: Granulocyte Colony-Stimulating Factor

PMN: Polymorphonuclear Leukocyte

SASP: Senescence-Associated Secretory Phenotype

L-MPs: Large Membrane Particles

TRAF6: TNF Receptor-Associated Factor 6

MCP-1: Monocyte Chemoattractant Protein-1

VEGFA: Vascular Endothelial Growth Factor A

BECN1: Beclin 1

HSP 70: Heat Shock Protein 70

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