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REVIEW article

Front. Neurol., 25 July 2025

Sec. Multiple Sclerosis and Neuroimmunology

Volume 16 - 2025 | https://doi.org/10.3389/fneur.2025.1611124

This article is part of the Research TopicBone Marrow Aging and its Impact on Immunosenescence in Neurological DiseasesView all 4 articles

Contemporary insights into neuroimmune interactions across development and aging


Xin Yi YeoXin Yi Yeo1Yunseon ChoiYunseon Choi1Yeonhee HongYeonhee Hong1Hyuk Nam Kwon,Hyuk Nam Kwon2,3Sangyong Jung
Sangyong Jung1*
  • 1Department of Medical Science, CHA University, Seongnam, Republic of Korea
  • 2School of Biological Science, University of Ulsan, Ulsan, Republic of Korea
  • 3Basic-Clinic Convergence Research Institute, University of Ulsan, Ulsan, Republic of Korea

Initially considered distinct systems with independent physiological functions, recent evidence highlights the crucial role of active crosstalk between the nervous and immune systems in regulating critical physiological and neurological processes and immunological homeostasis. The identification of a direct body-brain circuitry allowing the monitoring of peripheral inflammatory responses, a unique skull bone marrow source of immune cells to the central nervous system (CNS), and the physical interface of the blood-brain barrier with the meningeal system suggest direct intersystem interactions, which can be further modulated by the local tissue environment, allowing non-neurological factors to influence neurological outcomes and vice versa. While there is a recognized age-dependent decline in both neurological and immune system function, in part due to the natural accumulation of cellular defects and the development of chronic systemic inflammation, it is unclear if the pre-existing bidirectional feedback mechanisms between the neurological and peripheral immune system plays a role in shaping the system decline, beyond commonly investigated pathological conditions. In this review, we will explore the effect of aging on the bidirectional communication between the neurological and immunological systems and attempt to understand how the inevitable age-dependent alterations of the interaction may concurrently drive immunosenescence, normal neurological decline, and neuropathological progression.

1 Introduction

Humankind has long pursued the goal of extending both lifespan and healthspan, often through lifestyle modifications, diet interventions, or natural remedies aimed at counteracting diseases (1, 2), despite a limited understanding of the underlying causes of human mortality. Systemic scientific investigation into the mechanisms driving the time-dependent decline in physiological integrity began only about half a century ago, initially focusing on non-mammalian organisms (36) and cancer models (7, 8), which revealed that lifespan is under polygenic control. In recent years, it has become increasingly apparent that aging outcomes can be driven independently or in combination by physiological and pathological degenerative processes. Physiological aging is a universal process characterized by the gradual accumulation of damage in cellular structures and repair mechanisms (912). In contrast, pathological aging shares many of the molecular pathways of physiological aging but is further influenced by genetic predispositions and environmental factors that accelerate the decline of specific organ systems (13, 14). A comprehensive review of the hallmarks of aging has been provided by López-Otín et al. (15, 16).

The immune system is among the first system hit by aging and its associated process. Following puberty, the thymus undergoes a natural involution, leading to a marked decline in the production of non-self-reactive naïve T cell and the reduced capacity to respond to novel antigens (17). Although the T cells maturation can occur in secondary lymphoid organs such as the spleen and lymph nodes (18, 19), or in response to environmental cues (20), this process is significantly impaired with age. Chronic infections further deplete the naïve T cell pool and promote the accumulation of senescent and exhausted T-cell clones (21). This immunosensence is accompanied by an increased risk of autoimmunity due to the expansion of self-reactive T cells (22) a shift of self-reactive CD8+ T cells toward innate-like immune responses (23), heightened pro-inflammatory activity from autoreactive T cells (24), and impaired immune regulation, partially due to reduced recruitment of functional capacity of regulatory T cells (25, 26).

Experimental studies often examine immune function in isolation, focusing on individual immune components or on the role of systemic or neuroinflammation in the development and progression of neuropathology (27). However, the nervous system itself is an underappreciated yet critical regulator of systemic immune responses. To comprehensively understand how aging impacts immune function, as well as how bidirectional communication between the immune and nervous systems contributes to neurological disease, it is essential to elucidate the role of the immune mediators in neural function.

2 The interdependence of the nervous and immune system development and function

2.1 Contribution of the primitive immune system to early central nervous system (CNS) development and function

Although the immune and nervous systems originate from distinct embryonic tissues (28, 29), they develop concurrently and exert reciprocal reciprocal influences on each other's basal functional capacities. The central nervous system (CNS) harbors resident immune cells, derived from peripheral sources, that are essential for maintaining normal neurological function throughout life. Hematopoiesis begins in the yolk sac, giving rise to immune cells with structural and physiological functions but limited cytotoxic potential compared to those generated in the bone marrow. Fetal natural killer (NK) cells are predominantly localized in the choroid plexus and meninges during development (30). Dysregulation of their activity has been linked to cerebral malformations, potentially mediated by pleiotrophin secreted by NK cells (30), which influence neural stem cell differentiation (31, 32), neurite outgrowth (33), and synaptic function (34). These fetal NK cells are rapidly depleted over time and replaced by bone marrow-derived NK cells, particularly under inflammatory and pathological conditions. In contrast, fetal mast cells enter the brain as early as embryonic day 12.5 (E12.5) in mice. The contribute to brain vascular remodeling (35) and hormone-dependent sexual differentiation of the brain (36, 37). Unlike NK cells, these mast cells persist into adulthood, within the brain's pia matter and thalamus (38, 39). They retain fetal-like properties and may contribute to physiological neuroimmune regulation in unknown ways.

The earliest major immune cell infiltration into the CNS occurs around E9.5 in mice, when erythromyeloid progenitor-derived primitive macrophages interact with fibronectin on embryonic blood vessels via α5β1 integrin receptors, guiding their migration into the developing brain through the pial surface and leptomeninges (40, 41). Ablation of sodium-calcium exchanger 1 (NCX1) results in defective circulatory development and the absence of primitive macrophages in the embryonic brain despite normal yolk sac haematopoiesis (42), suggesting that physical circulation is essential for their migration toward the CNS. Within the embryonic brain, local sources of colony-stimulating factor 1 (CSF1) and interleukin 34 (IL-34) are necessary to activate colony-stimulating factor 1 receptor (CSF1R) signaling in the infiltrating macrophages, promoting their proliferation and long-term maintenance in the CNS (4346). Additionally, the interaction between C-X-C chemokine receptor 4(CXCR4) and its ligand CXCL12 directs immature macrophages toward the subventricular zone (SVZ) (47), where they engage with neural progenitors to modulate neurogenesis (48) (Figure 1). Transforming growth factor-β released by the neural precursors (NPC) further induces the expression of microglial identity genes (Sall1, Hexb, P2RY12), facilitating the differentiation of these primitive macrophages into microglia (49, 50).

Figure 1
Diagram illustrating microglia precursor formation and migration into the CNS. It shows developmental stages from hemangioblasts at E6.5-7.5 to primitive macrophages migrating to the CNS by E9.5-E19. It details interactions with endothelial cells via LFA-1 and CXCR4, and neural stem cell influence through CXCL12. Insets highlight immature and mature blood-brain barrier structures, including interactions with astrocytes, pericytes, and endothelial cells. The process showcases the changes from primitive to mature stages towards E14-19, emphasizing molecular components like ZO-1, claudin, and occludin.

Figure 1. Microglia dynamics during brain development. Primitive macrophage, the precursors of microglia, originate from the yolk sac and enters the developing brain at approximately E9.5 (top panel). These cells enter the developing brain primarily through the embryonic vasculature. The chemokine CXCL12, secreted by neural stem cells, guides the migration of primitive macrophages toward the interphase between the blood vasculature and the brain parenchyma. The lymphocyte function-associated antigen 1/Intercellular Adhesion Molecule-1 (LFA-1/ICAM-1) interaction is also proposed to facilitate trans-endothelial migration of these microglia precursors (middle panel). As the BBB matures between E14 and E19, tight junctions formed between endothelial cells, and astrocyte endfeet along with pericytes engage the vasculature, to reinforce barrier integrity. This results in a selective permeable interface that restricts the entry of peripheral immune cells into the CNS (bottom panel). Figure created with BioRender. Yeo, X. (2025) https://BioRender.com/uxni7uh.

The acquisition of microglia properties seems to be a largely context-specific phenomenon. Microglia retain several characteristics of peripheral macrophage, including their sensitivity toward cytokine and immune stimulus as well as their capacity to initiate immune responses in reaction to dynamic environmental conditions throughout life (51). The tightly regulated induction of programmed cell death in neural precursors (NPC) and newly generated neurons is essential for ensuring a quantitative match between the functional requirements of neuronal circuits and domains within the CNS (52, 53), and the elimination of excess or aberrant cells stochastically produced during the rapid process of neurogenesis (54). Microglia contribute to the pruning of NPCs and neurons through the release of proapoptotic factors that promote cell death via mechanisms independent of classical apoptosis (55, 56), caspase activation (57), excitotoxicity (58), or necroptosis (59). Damage-associated molecular patterns (DAMP) signals recruit microglia to the vicinity of aberrant cells, while additional molecular signals such as phosphatidylserine (54, 55) and calreticulin (55) mediate the phagocytic removal of damaged cells. Necroptotic microglia generated as a consequence of excessive phagocytic activity may themselves be removed by healthy microglia through C4b opsonization, thereby contributing to the maintenance of normal brain (56, 57).

Moreover, the release of purines, chemoattractant, and norepinephrine by neurons following changes in their activity (58), facilitates the redistribution of microglia within the brain parenchyma and supports microglia-dependent modulation of neuronal activity (59, 60). In a similar context, microglia play a pivotal role in the pruning and remodeling of synaptic contacts during neuronal circuit formation (61, 62). Disruption in microglia-neuron signaling between microglia and neurons that results in either excessive or insufficient synaptic pruning can lead to neuron structural dysfunction, a hallmark of various neurodevelopment and neurodegenerative disorders (63, 64). Despite substantial evidence linking altered microglial function to abnormal brain development (61, 6567), a recent study employing a CNS-specific microglia ablation model suggests that certain microglia-dependent neurodevelopmental processes may proceed in their absence (68). These findings underscore the need to revisit and rigorously re-evaluate the established paradigm regarding the role of microglia in neurodevelopment and neuronal circuit formation.

The entry of peripheral immune cells into the CNS becomes increasingly restricted from mid-gestation (E14-E19 in mice). This transition is marked by a downregulation of microglia α5β1 integrin expression (40) and an upregulation of anti-migratory protein p27 (69), both of which significantly reduce the motility and the subsequent infiltration of microglia precursors into the developing brain after E13.5. In addition, the tight junctions begin to form between the claudin-5 and occludin molecules localized to the apical membranes of endothelial cells (70). Alongside the recruitment of pericytes and the extension of astrocyte endfeet, these events lead to the establishment of the selectively permeable blood-brain barrier that functionally isolates the CNS from the peripheral immune system (71, 72). This barrier effectively restricts further migration of peripheral immune cells into the parenchyma and confines resident microglia within the CNS (Figure 1). Inflammation events occurring before the complete formation of the BBB is thought to “prime” primitive microglia and other resident immune cells, inducing a persistent activation state. The early priming may alter microglial immunophenotypes and increase the population of resident microglia that is maintained into adulthood (7375). Notably, a reservoir of cranial bone marrow-derived myeloid cell with immunoregulatory properties has been identified within the meningeal membrane (76, 77). These cells are situated adjacent to the glymphatic system, which serves as a conduit for the trafficking and interaction of peripheral immune cells with CNS-resident cell types (78). Intriguingly, immunogenic signals present in the cerebrospinal fluid (CSF) can be transmitted directly to the skull bone marrow, where they initiate local hematopoiesis before the activation of more distal sites such as the tibial marrow (79). The functional implication of this non-tibial immune cell source for the regulation and maintenance of neurological function remains largely unexplored.

2.2 Role of the immune system in peripheral nervous system (PNS) formation and the reciprocal role of the PNS for the CNS transmission of immune signals

The PNS provides an alternative pathway for neuroimmune interactions as the CNS becomes increasingly restrictive to peripheral immune cell infiltration. Neural crest cells (NCC), the progenitors of neurons in the PNS (80), detach from the neural plate and migrate outward along developing peripheral nerve tracts following neural tube closure, a process regulated bytranscriptional and epigenetic mechanisms (81) (Figure 2, top section). NCCs differentiate into four functionally overlapping populations of cells arrayed along the anteroposterior axis of the embryo, distinguished by differentially HOX gene paralog expression that that determines the fate and localization of NCC derivatives (82, 83). For example, vagal NCC, located between somite 1 and 7, gives rise to the enteric nervous system (84) and contribute to the development of the heart (85, 86), thymus (87), and pancreatic ganglia (88). Conversely, sympathetic neurons originate from trunk NCCs situated between somite 6 and 17 along the spinal cord (82). The progressive radial migration of NCCs, utlising existing neurons as scaffolds, coupled with sequential fate-restriction influenced by environmental cues, facilitates the establishment of CNS control over distant organs such as the gastrointestinal tract (89).

Figure 2
Diagram illustrating peripheral nervous system (PNS) formation and interactions with the peripheral immune system. It includes gene involvement, neural crest cell delamination, and the influence on migration and localization. The recruitment of immune cells and Schwann cells during nerve injury is shown in stages, highlighting roles of macrophages and repair processes.

Figure 2. Development of the PNS and immune system influence on its function. Embryonic development of the PNS, originating from neural crest cells that migrate and differentiate intro diverse neuronal and glial populations along peripheral nerve tracts (Top). Peripheral immune cells play a critical role in the regulation of PNS function and homeostasis. Although the contribution of immune cells to PNS development remains poorly understood, their involvement in peripheral nerve repair and regeneration following injury or under pathological systems is well-established (Bottom). Created with BioRender. Yeo, X. (2025) https://BioRender.com/uxni7uh.

Satellite glial cells derived from NCCs and residing in sensory and peripheral ganglia, are believed to function as resident immune-like cells, exhibiting macrophage-like properties including phagocytosis of cellular debris and pathogens (90). These cells express programmed death-ligand 1, which is critical for modulating surrounding T cell activity (91). Neuronal factors released by peripheral neurons modulate immune cell migration, activation, and local immune responses (92). In turn, immune cells proximal to the peripheral ganglia influence the development, maturation, and function of cytokine receptor-expressing peripheral neurons via cytokine signaling pathways (93, 94). An extensive review by Dr. von Andrian and his teamconsolidates current knowledge of the mechanisms underpinning peripheral neuroimmune interactions (95).

Within the PNS, neuropeptides play an important role in the modulation of tissue-resident immune cell function. Calcitonin gene-related peptide (CGRP) secreted by sensory TRPV1+ neurons upon detection of bacterial toxins, induces vasodilation, promotes keratinocyte proliferation to facilitate wound healing, and shapes immune responses by acting on Langerhans cells and dermal dendritic cells (96, 97). During Candida albicans skin infection, CGRPα stimulates IL-23 production by dermal dendritic cells, which in turn triggers IL-17A release from γδ T cells, thereby enhancing local antifungal immunity (98, 99). Simultaneously, CGRP reduces macrophage TNF-alpha production, inhibiting monocyte recruitment and preventing lymph node swelling (97). In allergic conditions such as those triggered by house dust mite exposure, peptidergic nociceptors release substance P, activating mast cells through Mas-related G-protein coupled receptor member B2 (MRGPRB2) signaling, and initiating allergic skin inflammation (100). TAFA chemokine-like family member 4 (TAFA4) produced by nociceptors promotes macrophage IL-10 secretion following ultraviolet-induced damage, supporting inflammation resolution and tissue repair (101). Nociceptors also regulate microfold (M) cell density and microbiota composition in the intestine to prevent pathogen invasion, with CGRP acting as a key modulator of these processes (102). Moreover, the Neuromedin U receptor signaling axis integrates enteric neuronal and innate immune responses to rapidly promote type 2 cytokine production, supporting tissue-protective immunity at mucosal surfaces (103, 104).

Afferent vagal neurons serve as a crucial communication pathway between peripheral immune cells and the brain, enabling the central nervous system to detect and respond to inflammatory signals. Broad vagal nerve stimulation has been shown to modulate systemic tumor necrosis factor α (TNF-α) levels following immune challenge (105, 106), suggesting the existence of an immunomodulatory network converging on the vagus nerve. Watkins et al. (107) further demonstrated that peripheral administration of the proinflammatory cytokine interleukin-1β (IL-1β) induces fever via vagal afferent pathways, highlighting the vagus nerve as a conduit for immune-to-brain signaling. The complex neuroimmunological effect of peripheral-derived cytokines, including their circulation, transport across the blood–brain barrier, and activation of circumventricular organs, requires careful consideration (108110). A recently described body-brain neural circuit encompasses immune-stimulus-evoked cytokine productionand distinct vagal sensory neuron populations that selectively respond discretely to anti-inflammatory cytokines (TRPA1 expressing neurons) or pro-inflammatory cytokines (CALCA expressing neurons). The peripheral immune status can be adaptively regulated through transcriptomic reprogramming of the sensory neurons (111) or through acetylcholine-dependent suppression of proinflammatory cytokine production by macrophages by efferent vagal fibers (105). Moreover, these vagal neurons direct innervate dopamine β-hydroxylase-expression neurons within the caudal nucleus of the solitary tract in the brainstem, mediating peripheral-to-central immune signaling and restoring of immune homeostasis after immune activation (112). Furthermore, gut microbiota and their metabolites, including bile acid derivatives (113), can differentially influence vagal neuron activity (114, 115). Consequently, the status of the peripheral immune system is intricately linked to neurological function and underpins the neurobehavioral and cognitive outcomes observed in health and disease.

2.3 Potential sensitivity of the immune system to neurological modulation

The development of the CNS and PNS occurs in parallel with early hematopoietic waves in the fetal yolk sac and liver, during which precursors of key innate and adaptive immune cell lineages including macrophages, NK cells, B cells, and T cells are generated. These immune cells begin colonizing various organs early in development but generally acquire full functional competence only after birth. As gestation progressed toward term, the bone marrow gradually assumes the role of the primary site for immune cell production and replenishment.

Regardless of their anatomical origin or functional maturity, developing immune cells express a diverse array of neurotransmitter receptors, offering a mechanistic basis for nervous system influence over immune system maturation and function (see Table 1). However, due to on the predominant reliance on adult models in immunological research, and the fact that initial yolk sac and liver-derived primitive immune populations are largely supplanted by bone marrow-derived cells, our understanding of the specific neurotransmitter receptor expression profiles in the earliest waves of immune cells remains limited. Nevertheless, characterizing the receptor profiles and functional responses of adult immune cells to neurotransmitters can provide valuable insights into potential neural mechanisms for immune regulation. Such regulation is likely to be organ and niche specific. Mature immune cells are also capable of synthesizing and releasing neurotransmitters (116, 117), adding further complexity to the bidirectional communication between the nervous and immune systems and underscoring the integrated nature of neuroimmune regulation.

Table 1
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Table 1. The expression of neurotransmitter receptors and their potential role in the regulation of immune cell maturation and function.

While the physiological regulation of immune cell activation remains an area requiring further investigation, the influence of injury and pathology on immune recruitment and response is well-established. Peripheral nerve repair following injury involves a finely orchestrated immune recruitment and response that is essential for successful nerve regeneration (Figure 2, bottom). Immediately after injury, damaged axons and Schwann cells release DAMPs, which activate resident macrophages and Schwann cells via TLRs, triggering the production of pro-inflammatory cytokines and chemokines that facilitate immune cell recruitment (118, 119). Circulating monocytes are rapidly recruited to the injury site and differentiate into macrophages in response to local signals, including colony-stimulating factor 1 (CSF1) (120). Neutrophils also transiently infiltrate the injured nerve, contributing to initial myelin clearance but are quickly replaced by longer-lasting macrophages (121). These recruited macrophages undergo a phenotypic transition from a pro-inflammatory M1 state to an anti-inflammatory and pro-regenerative M2-like state, marked by expression of IL-10, arginase-1, and growth factors such as insulin-like growth factor-1 and vascular endothelial growth factor (122). This phenotypic shift is critical for resolving inflammation and facilitating regeneration. Peripheral inflammatory events can alter CNS activity through the activation and sensitization of nociceptors, which transmit signals to the spinal cord and higher brain centers involved in pain and stress regulation (123, 124). In response, descending modulatory pathways, particularly those originating from the periaqueductal gray and rostral ventromedial medulla, influence spinal nociceptive processing and autonomic outflow. These descending circuits can indirectly modulate peripheral immune function via sympathetic and parasympathetic outputs, including the release of neurotransmitters such as norepinephrine and acetylcholine, which act on immune cells to regulate inflammation (125, 126).

Adult hematopoietic homeostasis depends on the coordinated self-renewal, differentiation, and mobilization of HSC within the bone marrow microenvironment (127), and their recruitment to peripheral sites in response to inflammatory cues (128, 129). The sympathetic nervous system is the principal neural regulation of bone physiology, including remodeling a hematopoietic function. Direct sympathetic innervation originating from the thoracolumbar spinal cord preganglionic neurons extends into bone tissue (130). These nerve fibers are closely associated with blood vessels and reside in the hematopoietic cavities of the bone marrow, forming neurovascular units (131). This anatomical arrangement suggests that peripheral nerve signals influence bone and marrow-resident cells via diffusible chemical mediators. Disruption of β adrenergic receptor signaling has been shown to impair bone accrual (132), hinder hematopoietic regeneration (133), and reduce mesenchymal stem cell motility (134). In addition, circadian oscillations of adrenergic tone regulate the proliferation and cyclic release of hematopoietic cells (135, 136), largely through modulation of CXCL12 expression by stromal cells (137, 138). Sympathetic denervation dampens CXCL12 expression and significantly impaired HSC mobilization (139). Furthermore, the rhythmic and noradrenaline-dependent expression of endothelial adhesion molecules (140) emphasizes the role of adrenergic signaling and circadian timing in governing HSC trafficking and localization within the bone marrow niche. In contrast, the parasympathetic nervous system contributes choline acetyltransferase (ChAT)-positive fibers, likely originating from skeletal nerves (141), that have been implicated in linking physical activity to bone homeostasis. The precise role of parasympathetic innervation in the regulation of hematopoiesis remains undefined.

The establishment of multiple neuroimmune interaction nodes during development creates enduring sites for nervous system influence on immune regulation. Given the close physical and biochemical interactions between the immune cells and neurons, and their shared capacity to produce and respond to a common set of chemical messengers, age, and environmental-dependent alterations to the microenvironment inevitably the functionality of both systems. Therefore, the dynamic evolution of neural function and pathology must be interpreted in tandem with the context-dependent modulation of these neuroimmune interfaces.

3 Impact of aging on immune and nervous system function

3.1 Immunosenescence and inflammaging: mechanisms and consequences

The immune system undergoes a progressive functional decline with age, independent of the nervous system, characterized by both quantitative and qualitative shifts in innate and adaptive immunity. This decline compromises the body's ability to combat pathogens (142, 143). While the number of innate immune cells such as the macrophages (microglia in the CNS) and neutrophils remains relatively stable with age (144146), their chemotactic and phagocytic capacity diminish (147) along with reduced cellular turnover (148). These defects result in increased accumulation of cellular debris (149) and impaired resolution of infections and inflammatory conditions (150, 151).

Age-associated alterations in cytokine production (152), toll-like receptor (TLR) signaling in response to pathogens (153), and impaired recruitment and migration of immune cells (154) further contribute to the state of persistent, low-grade immune activation that reflects a failed attempt to resolve chronic inflammation and infection. In parallel, thymic involution leads to marked reduction, and eventual cessation of naïve T cell production (155). Compounding this is the depletion of existing T cells due to repeated infections (156) and their subsequent clonal expansion and exhaustion, which attempts to compensate for impaired thymic output (157, 158). These factors contribute to telomere attrition and DNA damage, disrupting T cell homeostasis and survival (159, 160).

HSC in the aging bone marrow exhibit a skewed differentiation bias favoring myeloid over lymphoid lineages (161), coupled with reduced expression of activation-induced cytidine deaminase, an enzyme critical for antibody class switching (162). Consequently, aged individuals produced higher numbers of immature naïve B cells with diminished capacity to mount specific, long-term responses against novel antigens. In contrast, the adult skull bone marrow niche which is protected from systemic aging (163), and exhibiting differential responses to pathology compared to femoral bone marrow (164), may play a unique and as yet poorly understood role in CNS immune aging. The cumulation of these cellular and molecular changes in the peripheral immune system leads to immune competence, accumulation of tissue damage, increased risk of age-related complications, and elevated mortality.

Beyond impaired host defense, the aging immune system actively drives systemic aging. Chronically activated immune cells produce pro-inflammatory cytokines that damage tissues across multiple systems–including the nervous, musculoskeletal, and cardiovascular systems—via chronic inflammation of “inflammaging” (165). In the CNS, senescent microglia are implicated in neurodegeneration. These aged microglia display impaired clearance of protein aggregates (166), reduced motility, and compromised phagocytic activity, coinciding with a dystrophic morphology (167), loss of homeostatic gene expression (168), and metabolic shift toward fatty acid metabolism (169). The accumulation of lipid droplets further impairs debris clearance, including myelin remnants (170). Activated microglia induce a A1 phenotype in astrocytes via interleukin 1α (IL-1α), TNFα, and complement component (C1q) signaling (171), prompting astrocytes to secrete chemokines such as CXCL10 that attract T cells into the CNS through an increasingly permeable BBB (172, 173). This cascade sustains local neuroinflammation, activates resident glia, and promotes neuronal dysfunction and death.

In the musculoskeletal system, inflammaging disrupts the regulatory balance between interleukin 6 (IL-6) and myostatin, impairing the regenerative capacity of muscle satellite cells (174176). IL-6 activates catabolic signaling via the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, inhibiting satellite cell differentiation and increasing myostatin expression (177), which in turn activates small mothers against decapentaplegic 2/3 (Smad2/3) signaling and induces cell cycle arrest (178). These changes reduce satellite cell proliferation, exacerbating sarcopenia and chronic inflammation (175, 179). In the adipose tissue, aging and metabolic dysfunction promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation (180), while targeting sirtuin 2, deacetylase regulating NLRP3, has been shown to reverse insulin resistance in aged mice (181). This highlights a tissue-specific interplay between immune dysfunction and metabolic disorders. Moreover, altered PNS function may modulate these immune responses, contributing to organ-specific degeneration and failure (182184).

Recent studies have also highlighted the gut–immune–brain axis as a key player in immunosenescence and inflammaging (185187). Aging-associated gut dysbiosis compromises intestinal immune homeostasis and increases gut permeability, facilitating the translocation of microbial products such as lipopolysaccharides (LPS) into systemic circulation (188, 189). Conversely, peripheral neuron activity may shape gut microbiota composition (190). These microbial-derived inflammatory cues perpatuate immune dysregulation. Interventions with probiotic and prebiotic aimed at restoring gut microbiota balance may mitigate this systemic inflammation (191). Collectively, these findings underscore the intricate interplay between immunosenescence, chronic inflammation, and systemic aging. They highlight the need for therapeutic strategies targeting immune rejuvenation to delay or prevent age-related diseases.

3.2 Impact of age-dependent systemic changes on neurological decline and neuropathology development

Endothelial cell senescence is a key contributor to age-associated BBB dysfunction. This process disrupts the formation of the endothelial glycocalyx (192) and downregulates the expression of tight junction proteins (193), leading to increased BBB permeability. The extent of BBB leakage is strongly correlated with changes in tight junction protein expression (194). Notably, the overexpression or pharmacological activation of silent information regulator 1 (Sirt1) has been shown to preserve BBB integrity in aging models, likely through attenuation of reactive oxygen species production and preservation of endothelial cell dysfunction (195, 196). Additional pathological changes, such as the accumulation of CNS-derived protein aggregates in pericytic (197), the loss of pericyte-astrocyte interactions (198, 199), impaired glymphatic waste clearance (200, 201), and sustained systemic inflammation (202). This disruption permits the infiltration of dysfunctional and pro-inflammatory peripheral immune cells into the CNS (203) (Figure 3). In synergy with chronically activated aged microglia and astrocytes, these infiltrating immune cells exacerbate neuroinflammation, compromise neuronal function, impair synapse maintenance, and potentiate the neurotoxic effects of abnormal protein aggregates, thereby accelerating neuropathological progression (139).

Figure 3
Diagram illustrating inflammation's effect on the brain. Neutrophils and leukocytes infiltrate through a damaged blood-brain barrier, leading to reactive astrocytes and activated microglia. Proinflammatory cytokines escalate, enhancing the pro-inflammatory response. Microglia shift from M0 to M1 or M2 states, contributing to neuroinflammation. Healthy neurons, affected by NMDA receptor activation, undergo neurodegeneration.

Figure 3. Age-related changes in immune cells and the development of chronic inflammation in the CNS. Increased permeability of the BBB due to endothelial cell, pericyte, and astrocyte senescence and demise and an increase in the number of activated astrocytes and microglia leads to the recruitment of peripheral immune cells into the brain parenchyma. The altered immune cell (from periphery or resident to the brain) function and status with age results in the accumulation of senescent cells, cellular debris, and abnormally aggregated proteins, triggering further inflammatory responses within the brain. As such, the persistent inflammatory status and increasingly abundant cellular byproducts result in a positive feedback loop that damages and triggers death pathways in neurons (neurodegeneration). Created in BioRender. Yeo, X. (2025) https://BioRender.com/dwabb60.

Cognitive decline in aging is further linked to persistent, low-grade neuroinflammation arising from complex bidirectional interactions between the CNS and the gut microbiota. Monocyte-driven gastrointesinal inflammation can increase gut permeability, enabling translocation of microbial products into circulation, which subsequently impacts the CNS (204). Aged mice exhibit elevated levels of circulating and brain-associated lipopolysaccharide (LPS), along with increased expression of Toll-like receptor 4 (TLR4), myeloid differentiation protein-88 (MyD88), and nuclear translocation of NF-κB in both intestinal and brain tissues (205). Moreover, Microbiome gut microbiota-derived short-chain fatty acids and metabolites such as 3-indoxyl sulfate can stimulate vagal nerve and NST activity (206), potentially modulating systemic and central inflammation via vagal pathways. The exacerbation of motor deficits in α-synuclein-expressing mice following fecal microbiota transplantation from Parkinson's disease (PD) patients suggests a potent gene-environment interaction in neurodegenerative disease pathogenesis (207).

Systemic metabolic and hormonal alterations further compromise neural function with age. Immune-metabolic crosstalk and cytokine-mediated interference in metabolic regulation contribute to the development of insulin resistance (208), ectopic lipid deposition (209, 210), and hypertension (211). Each of these factors independently heightens the risk for neuronal death and cognitive impairment (212214). The decline in hormone levels with age further exacerbates deficits in glucose metabolism and sensing (215, 216) and inflammaging worsens existing defects in glucose metabolism and sensing (217). Of the earliest detactable changes in this cascade is the downregulation of glucose transporter type 4 (Glut4) expression in insulin-sensitive neurons (218, 219), which compromises synaptic energy supply (220) leading to cognitive dysfunction. Chronic hyperglycaemia also promotes tau hyperphosphorylation, a hallmark of Alzheimer's disease (221). In comparison, hypertension and dyslipidemia impair cerebral blood flow, increasing the risk of hypoperfusion-induced microinfarcts (222). Comprehensive investigation of the interplay between immune dysregulation, metabolic dysfunction, and neural decline is essential to delineate the mechanisms driving age-related neuropathology.

4 Modulation of the neuroimmune axis holds promise for the management and treatment of neurological pathology

Targeting the neuroimmune axis presents a promising approach for the treatment of neurological disorders. One such strategy involves the clearance of senescent immune cells using senolytic agents, which has demonstrated neuroprotective effects. The elimination of senescent immune cells with the use of senolytics has been shown to mitigate neurological decline by enhancing neuronal survival toward physical insults (223), reducing proinflammatory cytokine production (224) and abnormal protein aggregation (225) in the presence of neuroinflammation. As brain penetrant and non-penetrant senolytics are equally effective in reducing Ad pathology, the locus and mechanism of effect are unclear (226). Yet, care is required for the use of senolytics in the management of immune-related conditions with their potential for off-target toxicity (227). The heterogeneity of cellular senescence (228, 229) and specificity of senolytics to survival pathways also meant that there is no universal senolytic to clear all senescence cells and the potential unwanted removal of senescent, non-replaceable neurons may exert more harm to neurological function and neurocognitive outcomes.

Alternatively, anti-inflammatory therapies targeting neuroinflammation, a key driver of neurodegeneration can be achieved by modulating microglia activation (230), reducing prostaglandin-mediated inflammation (231), and inhibiting the complement system (232). The long-term use of non-steroidal anti-inflammatory drugs (NSAID) that target cyclooxygenases (COX) and the production of prostaglandin (233) is associated with a significant decrease in the risk of developing AD (234). Consistent with the observation, COX-2 inhibition prevents progressive degeneration of dopaminergic neurons in a preclinical model of Parkinson's disease (PD) (235). The inhibition of NLRP3 inflammasome with mefenamic acid and the complement pathway with anti-complement drugs have ameliorated amyloid beta deposition, synapse loss, and neuronal loss, and improved neurocognitive outcomes of genetic models of neurodegenerative disease (236, 237). The chronic use of NSAID risks gastrointestinal and renal toxicity (238, 239) while general inhibition of inflammation is likely effective only pre-symptomatically.

Glucagon-like peptide 1 (GLP1) agonist exerts a pleiotropic effect in the CNS to reduce inflammation and abnormal protein aggregation. Liraglutide treatment significantly reduced inflammation in the cortex of the APP/PS1 mouse model of AD (240) while Exenatide reduced TNFα expression and hippocampal neuron loss in a streptozotocin model of AD (241). On the other hand, GLP1 agonists may enhance autophagy and Aβ plaque clearance (242), improve brain insulin sensitivity and availability of glucose to neurons (243), and boost brain-derived neurotrophic factor (BDNF) signaling (244) to increase the chance for neuron survival in the presence of neuroinflammation and toxic protein aggregates. The time and dose of GLP1 administered is important for the greatest efficacy in the management of neurological conditions and the co-administration with anti-amyloid drugs may enhance the neuroprotective effect of GLP1 agonists in neurodegenerative diseases.

Given the absence of a modifying treatment for neurodegenerative diseases, lifestyle factors are an appealing strategy to manage progressive neurocognitive decline. Lifestyle changes have been linked to better cognitive functions in older individuals (245). Despite the difference in targets, common dietary interventions that limit saturated fats and processed food consumption (Mediterranean diet), induce ketosis (ketogenic diet), and restrict energy consumption (caloric restriction or intermittent fasting) aimed to increase the availability of the precursors essential for cellular recovery, reduce factors inflicted in cellular death in neurodegenerative conditions, and enhance autophagy to promote the clearance of protein aggregates (246, 247). Optimal diets vary greatly depending on the underlying genetics and disease stage of an individual and long-term adherence to a restrictive diet is challenging. The adoption of physical activity in various modalities is capable of slowing cognitive decline in patients with mild cognitive impairment and AD (248) through the expression of BDNF (249) and alleviation of neuroinflammation (250).

5 Conclusion

Modulating neuroimmune interactions offers a compelling strategy for the treatment of diverse neurological pathologies through the alteration of disease trajectories, alleviation of symptoms, and improving quality of life. Nonetheless, the heterogeneity of neuroimmune responses and disease status across individuals complicates treatment development. General immunosuppression carries risks of infection and malignancy while CNS-targeted therapies need to cross the BBB, and a delicate tuning of immune suppression is essential to maintain key immune functions while alleviating neurological defects. The development of reliable biomarkers to stratify patients, monitor neuroimmune activity, and assess therapeutic response is essential to the implementation of precision medicine approaches. Advances in nanotechnology and drug delivery systems may also enhance the precision and safety of neuroimmune-targeting interventions. Ultimately, the successful translation of neuroimmune modulation into clinical practice will depend on sustained interdisciplinary research. Collaborative efforts integrating immunology, neuroscience, metabolism, pharmacology, and systems biology are essential to unravel the complex interplay between systemic aging and neurological decline. By deepening our understanding of the neuroimmune axis, it may be possible to identify novel therapeutic targets and intervention windows that can halt or even reverse the progression of neurodegenerative diseases, offering hope for effective and individualized treatments in the aging population.

Author contributions

XY: Conceptualization, Writing – original draft, Writing – review & editing. YC: Writing – original draft. YH: Writing – original draft. HK: Writing – review & editing. SJ: Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. SJ was supported by the Industry-Academic Cooperation Foundation CHA University grant (CHA-202300230001 and CHA-202500040001).

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.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement

The author(s) declare that no Gen AI was used in the creation of this manuscript.

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References

1. Kloc J. What Have We Learned From Centuries of Chasing Immortality? The New York Times (2025). Available online at: https://www.nytimes.com/2025/01/18/well/longevity-history.html (Accessed April 7, 2025).

Google Scholar

2. Cong W, Chen K. Traditional Chinese medicine and aging: integration and collaboration promotes healthy aging. Aging Med. (2019) 2:139–41. doi: 10.1002/agm2.12077

PubMed Abstract | Crossref Full Text | Google Scholar

3. Klass MR. A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech Ageing Dev. (1983) 22:279–86. doi: 10.1016/0047-6374(83)90082-9

PubMed Abstract | Crossref Full Text | Google Scholar

4. Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize, tetrahymena and yeast to human cancer and aging. Nat Med. (2006) 12:1133–8. doi: 10.1038/nm1006-1133

PubMed Abstract | Crossref Full Text | Google Scholar

5. Boulias K, Horvitz HR. The C. elegans microRNA mir-71 acts in neurons to promote germline-mediated longevity through regulation of DAF-16/FOXO. Cell Metab. (2012) 15:439–50. doi: 10.1016/j.cmet.2012.02.014

PubMed Abstract | Crossref Full Text | Google Scholar

6. Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper MD, et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. (2011) 477:482–5. doi: 10.1038/nature10296

PubMed Abstract | Crossref Full Text | Google Scholar

7. Baker DJ, Dawlaty MM, Wijshake T, Jeganathan KB, Malureanu L, Van Ree JH, et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol. (2013) 15:96–102. doi: 10.1038/ncb2643

PubMed Abstract | Crossref Full Text | Google Scholar

8. Bernardes De Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. (2012) 4:691–704. doi: 10.1002/emmm.201200245

PubMed Abstract | Crossref Full Text | Google Scholar

9. Miller KN, Victorelli SG, Salmonowicz H, Dasgupta N, Liu T, Passos JF, et al. Cytoplasmic DNA: sources, sensing, and role in aging and disease. Cell. (2021) 184:5506–26. doi: 10.1016/j.cell.2021.09.034

PubMed Abstract | Crossref Full Text | Google Scholar

10. Nik-Zainal S, Hall BA. Cellular survival over genomic perfection. Science. (2019) 366:802–3. doi: 10.1126/science.aax8046

PubMed Abstract | Crossref Full Text | Google Scholar

11. Sanchez-Contreras M, Kennedy SR. The complicated nature of somatic mtDNA mutations in aging. Front Aging. (2022) 2:805126. doi: 10.3389/fragi.2021.805126

PubMed Abstract | Crossref Full Text | Google Scholar

12. Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science. (2015) 350:1193–8. doi: 10.1126/science.aab3389

PubMed Abstract | Crossref Full Text | Google Scholar

13. Halliday M, Hughes D, Mallucci GR. Fine-tuning PERK signaling for neuroprotection. J Neurochem. (2017) 142:812–26. doi: 10.1111/jnc.14112

PubMed Abstract | Crossref Full Text | Google Scholar

14. Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol. (2019) 20:421–35. doi: 10.1038/s41580-019-0101-y

PubMed Abstract | Crossref Full Text | Google Scholar

15. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. (2013) 153:1194–217. doi: 10.1016/j.cell.2013.05.039

PubMed Abstract | Crossref Full Text | Google Scholar

16. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. (2023) 186:243–78. doi: 10.1016/j.cell.2022.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

17. Liang Z, Dong X, Zhang Z, Zhang Q, Zhao Y. Age-related thymic involution: mechanisms and functional impact. Aging Cell. (2022) 21:e13671. doi: 10.1111/acel.13671

PubMed Abstract | Crossref Full Text | Google Scholar

18. Bousso P. T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol. (2008) 8:675–84. doi: 10.1038/nri2379

PubMed Abstract | Crossref Full Text | Google Scholar

19. Martins-Filho O, Mello J, Correa-Oliveira R. The spleen is an important site of T cell activation during human hepatosplenic schistosomiasis. Mem Inst Oswaldo Cruz. (1998) 93:159–64. doi: 10.1590/S0074-02761998000700023

PubMed Abstract | Crossref Full Text | Google Scholar

20. Chen W, Jin W, Hardegen N, Lei K-J, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med. (2003) 198:1875–86. doi: 10.1084/jem.20030152

PubMed Abstract | Crossref Full Text | Google Scholar

21. Gress RE, Deeks SG. Reduced thymus activity and infection prematurely age the immune system. J Clin Invest. (2009) 119:2884–7. doi: 10.1172/JCI40855

PubMed Abstract | Crossref Full Text | Google Scholar

22. Prelog M. Aging of the immune system: a risk factor for autoimmunity? Autoimmun Rev. (2006) 5:136–9. doi: 10.1016/j.autrev.2005.09.008

PubMed Abstract | Crossref Full Text | Google Scholar

23. Ju YJ, Lee SW, Kye YC, Lee GW, Kim HO, Yun CH, et al. Self-reactivity controls functional diversity of naive CD8+ T cells by co-opting tonic type I interferon. Nat Commun. (2021) 12:6059. doi: 10.1038/s41467-021-26351-3

PubMed Abstract | Crossref Full Text | Google Scholar

24. Coder BD, Wang H, Ruan L, Su DM. Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation. J Immunol. (2015) 194:5825–37. doi: 10.4049/jimmunol.1500082

PubMed Abstract | Crossref Full Text | Google Scholar

25. Thomas R, Oh J, Wang W, Su D. Thymic atrophy creates holes in Treg-mediated immuno-regulation via impairment of an antigen-specific clone. Immunology. (2021) 163:478–92. doi: 10.1111/imm.13333

PubMed Abstract | Crossref Full Text | Google Scholar

26. Palatella M, Guillaume SM, Linterman MA, Huehn J. The dark side of Tregs during aging. Front Immunol. (2022) 13:940705. doi: 10.3389/fimmu.2022.940705

PubMed Abstract | Crossref Full Text | Google Scholar

27. Passaro AP, Lebos AL, Yao Y, Stice SL. Immune response in neurological pathology: emerging role of central and peripheral immune crosstalk. Front Immunol. (2021) 12:676621. doi: 10.3389/fimmu.2021.676621

PubMed Abstract | Crossref Full Text | Google Scholar

28. Anastassova-Kristeva M. The origin and development of the immune system with a view to stem cell therapy. J Hematother Stem Cell Res. (2003) 12:137–54. doi: 10.1089/152581603321628287

PubMed Abstract | Crossref Full Text | Google Scholar

29. Ansari A, Pillarisetty LS. Embryology, Ectoderm. In: StatPearls. Treasure Island, FL: StatPearls Publishing (2025). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK539836/; https://www.ncbi.nlm.nih.gov/books/NBK431128/ (Accessed April 9, 2025).

Google Scholar

30. Ning Z, Liu Y, Guo D, Lin WJ, Tang Y. Natural killer cells in the central nervous system. Cell Commun Signal. (2023) 21:341. doi: 10.1186/s12964-023-01324-9

PubMed Abstract | Crossref Full Text | Google Scholar

31. Fu B, Zhou Y, Ni X, Tong X, Xu X, Dong Z, et al. Natural killer cells promote fetal development through the secretion of growth-promoting factors. Immunity. (2017) 47:1100–13.e6. doi: 10.1016/j.immuni.2017.11.018

PubMed Abstract | Crossref Full Text | Google Scholar

32. Hienola A, Pekkanen M, Raulo E, Vanttola P, Rauvala H. HB-GAM inhibits proliferation and enhances differentiation of neural stem cells. Mol Cell Neurosci. (2004) 26:75–88. doi: 10.1016/j.mcn.2004.01.018

PubMed Abstract | Crossref Full Text | Google Scholar

33. Yanagisawa H, Komuta Y, Kawano H, Toyoda M, Sango K. Pleiotrophin induces neurite outgrowth and up-regulates growth-associated protein (GAP)-43 mRNA through the ALK/GSK3β/β-catenin signaling in developing mouse neurons. Neurosci Res. (2010) 66:111–6. doi: 10.1016/j.neures.2009.10.002

PubMed Abstract | Crossref Full Text | Google Scholar

34. González-Castillo C, Ortuño-Sahagún D, Guzmán-Brambila C, Pallàs M, Rojas-Mayorquín AE. Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus. Front Cell Neurosci. (2015) 8:443. doi: 10.3389/fncel.2014.00443

PubMed Abstract | Crossref Full Text | Google Scholar

35. Chia SL, Kapoor S, Carvalho C, Bajénoff M, Gentek R. Mast cell ontogeny: from fetal development to life-long health and disease. Immunol Rev. (2023) 315:31–53. doi: 10.1111/imr.13191

PubMed Abstract | Crossref Full Text | Google Scholar

36. Lenz KM, Pickett LA, Wright CL, Davis KT, Joshi A, McCarthy MM. Mast cells in the developing brain determine adult sexual behavior. J Neurosci. (2018) 38:8044–59. doi: 10.1523/JNEUROSCI.1176-18.2018

PubMed Abstract | Crossref Full Text | Google Scholar

37. Lenz KM, Pickett LA, Wright CL, Galan A, McCarthy MM. Prenatal allergen exposure perturbs sexual differentiation and programs lifelong changes in adult social and sexual behavior. Sci Rep. (2019) 9:4837. doi: 10.1038/s41598-019-41258-2

PubMed Abstract | Crossref Full Text | Google Scholar

38. Tanioka D, Chikahisa S, Shimizu N, Shiuchi T, Sakai N, Nishino S, et al. Intracranial mast cells contribute to the control of social behavior in male mice. Behav Brain Res. (2021) 403:113143. doi: 10.1016/j.bbr.2021.113143

PubMed Abstract | Crossref Full Text | Google Scholar

39. Li Y, Di C, Song S, Zhang Y, Lu Y, Liao J, et al. Choroid plexus mast cells drive tumor-associated hydrocephalus. Cell. (2023) 186:5719–38.e28. doi: 10.1016/j.cell.2023.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

40. Smolders SM, Swinnen N, Kessels S, Arnauts K, Smolders S, Le Bras B, et al. Age-specific function of α5β1 integrin in microglial migration during early colonization of the developing mouse cortex. Glia. (2017) 65:1072–88. doi: 10.1002/glia.23145

PubMed Abstract | Crossref Full Text | Google Scholar

41. Navascués J, Calvente R, Marín-Teva JL, Cuadros MA. Entry, dispersion and differentiation of microglia in the developing central nervous system. An Acad Bras Ciênc. (2000) 72:91–102. doi: 10.1590/S0001-37652000000100013

PubMed Abstract | Crossref Full Text | Google Scholar

42. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. (2010) 330:841–5. doi: 10.1126/science.1194637

PubMed Abstract | Crossref Full Text | Google Scholar

43. Dalmau I, Vela JM, González B, Finsen B, Castellano B. Dynamics of microglia in the developing rat brain. J Comp Neurol. (2003) 458:144–57. doi: 10.1002/cne.10572

PubMed Abstract | Crossref Full Text | Google Scholar

44. Nikodemova M, Kimyon RS De I, Small AL, Collier LS, Watters JJ. Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week. J Neuroimmunol. (2015) 278:280–8. doi: 10.1016/j.jneuroim.2014.11.018

PubMed Abstract | Crossref Full Text | Google Scholar

45. Green KN, Crapser JD, Hohsfield LA. To kill a microglia: a case for CSF1R inhibitors. Trends Immunol. (2020) 41:771–84. doi: 10.1016/j.it.2020.07.001

PubMed Abstract | Crossref Full Text | Google Scholar

46. Wu S, Xue R, Hassan S, Nguyen TML, Wang T, Pan H, et al. Il34-Csf1r pathway regulates the migration and colonization of microglial precursors. Dev Cell. (2018) 46:552–63.e4. doi: 10.1016/j.devcel.2018.08.005

PubMed Abstract | Crossref Full Text | Google Scholar

47. Arnò B, Grassivaro F, Rossi C, Bergamaschi A, Castiglioni V, Furlan R, et al. Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex. Nat Commun. (2014) 5:5611. doi: 10.1038/ncomms6611

PubMed Abstract | Crossref Full Text | Google Scholar

48. Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP, et al. Microglia instruct subventricular zone neurogenesis. Glia. (2006) 54:815–25. doi: 10.1002/glia.20419

PubMed Abstract | Crossref Full Text | Google Scholar

49. Hattori Y, Kato D, Murayama F, Koike S, Asai H, Yamasaki A, et al. CD206+ macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia. Cell Rep. (2023) 42:112092. doi: 10.1016/j.celrep.2023.112092

PubMed Abstract | Crossref Full Text | Google Scholar

50. Fixsen BR, Han CZ, Zhou Y, Spann NJ, Saisan P, Shen Z, et al. SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity. Nat Immunol. (2023) 24:1188–99. doi: 10.1038/s41590-023-01528-8

PubMed Abstract | Crossref Full Text | Google Scholar

51. Grassivaro F, Menon R, Acquaviva M, Ottoboni L, Ruffini F, Bergamaschi A, et al. Convergence between microglia and peripheral macrophages phenotype during development and neuroinflammation. J Neurosci. (2020) 40:784–95. doi: 10.1523/JNEUROSCI.1523-19.2019

PubMed Abstract | Crossref Full Text | Google Scholar

52. Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci. (1991) 14:453–501. doi: 10.1146/annurev.ne.14.030191.002321

PubMed Abstract | Crossref Full Text | Google Scholar

53. Priya R, Paredes MF, Karayannis T, Yusuf N, Liu X, Jaglin X, et al. Activity regulates cell death within cortical interneurons through a calcineurin-dependent mechanism. Cell Rep. (2018) 22:1695–709. doi: 10.1016/j.celrep.2018.01.007

PubMed Abstract | Crossref Full Text | Google Scholar

54. Brelstaff J, Tolkovsky AM, Ghetti B, Goedert M, Spillantini MG. Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep. (2018) 24:1939–48.e4. doi: 10.1016/j.celrep.2018.07.072

PubMed Abstract | Crossref Full Text | Google Scholar

55. Reid KM, Kitchener EJA, Butler CA, Cockram TOJ, Brown GC. Brain cells release calreticulin that attracts and activates microglia, and inhibits amyloid beta aggregation and neurotoxicity. Front Immunol. (2022) 13:859686. doi: 10.3389/fimmu.2022.859686

PubMed Abstract | Crossref Full Text | Google Scholar

56. Bennett FC, Bennett ML. Microglia cannibalism during neurodevelopment results in necroptotic cell death. PLoS Biol. (2024) 22:e3002869. doi: 10.1371/journal.pbio.3002869

PubMed Abstract | Crossref Full Text | Google Scholar

57. Zhou T, Li Y, Li X, Zeng F, Rao Y, He Y, et al. Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice. Nat Commun. (2022) 13:6233. doi: 10.1038/s41467-022-33932-3

PubMed Abstract | Crossref Full Text | Google Scholar

58. Umpierre AD, Wu L. How microglia sense and regulate neuronal activity. Glia. (2021) 69:1637–53. doi: 10.1002/glia.23961

PubMed Abstract | Crossref Full Text | Google Scholar

59. Li Y, Du X-F, Liu C-S, Wen Z-L, Du J-L. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell. (2012) 23:1189–202. doi: 10.1016/j.devcel.2012.10.027

PubMed Abstract | Crossref Full Text | Google Scholar

60. Stowell RD, Sipe GO, Dawes RP, Batchelor HN, Lordy KA, Whitelaw BS, et al. Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Nat Neurosci. (2019) 22:1782–92. doi: 10.1038/s41593-019-0514-0

PubMed Abstract | Crossref Full Text | Google Scholar

61. Weinhard L, Di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun. (2018) 9:1228. doi: 10.1038/s41467-018-03566-5

PubMed Abstract | Crossref Full Text | Google Scholar

62. Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, et al. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell. (2020) 182:388–403.e15. doi: 10.1016/j.cell.2020.05.050

PubMed Abstract | Crossref Full Text | Google Scholar

63. Hu C, Li H, Li J, Luo X, Hao Y. Microglia: synaptic modulator in autism spectrum disorder. Front Psychiatry. (2022) 13:958661. doi: 10.3389/fpsyt.2022.958661

PubMed Abstract | Crossref Full Text | Google Scholar

64. Triviño JJ, von Bernhardi R. The effect of aged microglia on synaptic impairment and its relevance in neurodegenerative diseases. Neurochem Int. (2021) 144:104982. doi: 10.1016/j.neuint.2021.104982

PubMed Abstract | Crossref Full Text | Google Scholar

65. Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci. (2012) 32:15106–11. doi: 10.1523/JNEUROSCI.1167-12.2012

PubMed Abstract | Crossref Full Text | Google Scholar

66. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. (2007) 131:1164–78. doi: 10.1016/j.cell.2007.10.036

PubMed Abstract | Crossref Full Text | Google Scholar

67. Favuzzi E, Huang S, Saldi GA, Binan L, Ibrahim LA, Fernández-Otero M, et al. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell. (2021) 184:5686. doi: 10.1016/j.cell.2021.10.009

PubMed Abstract | Crossref Full Text | Google Scholar

68. O'Keeffe M, Booker SA, Walsh D, Li M, Henley C, Simões De Oliveira L, et al. Typical development of synaptic and neuronal properties can proceed without microglia in the cortex and thalamus. Nat Neurosci. (2025) 28:268–79. doi: 10.1038/s41593-024-01833-x

PubMed Abstract | Crossref Full Text | Google Scholar

69. Beeken J, Kessels S, Rigo JM, Alpizar YA, Nguyen L, Brône B. p27kip1 modulates the morphology and phagocytic activity of microglia. Int J Mol Sci. (2022) 23:10432. doi: 10.3390/ijms231810432

PubMed Abstract | Crossref Full Text | Google Scholar

70. Menaceur C, Gosselet F, Fenart L, Saint-Pol J. The blood-brain barrier, an evolving concept based on technological advances and cell-cell communications. Cells. (2021) 11:133. doi: 10.3390/cells11010133

PubMed Abstract | Crossref Full Text | Google Scholar

71. Kubotera H, Ikeshima-Kataoka H, Hatashita Y, Allegra Mascaro AL, Pavone FS, Inoue T. Astrocytic endfeet re-cover blood vessels after removal by laser ablation. Sci Rep. (2019) 9:1263. doi: 10.1038/s41598-018-37419-4

PubMed Abstract | Crossref Full Text | Google Scholar

72. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature. (2010) 468:562–6. doi: 10.1038/nature09513

PubMed Abstract | Crossref Full Text | Google Scholar

73. Shimamura T, Kitashiba M, Nishizawa K, Hattori Y. Physiological roles of embryonic microglia and their perturbation by maternal inflammation. Front Cell Neurosci. (2025) 19:1552241. doi: 10.3389/fncel.2025.1552241

PubMed Abstract | Crossref Full Text | Google Scholar

74. LaMonica Ostrem BE, Domínguez-Iturza N, Stogsdill JA, Faits T, Kim K, Levin JZ, et al. Fetal brain response to maternal inflammation requires microglia. Development. (2024) 151:dev202252. doi: 10.1242/dev.202252

PubMed Abstract | Crossref Full Text | Google Scholar

75. Msallam R, Balla J, Rathore APS, Kared H, Malleret B, Saron WAA, et al. Fetal mast cells mediate postnatal allergic responses dependent on maternal IgE. Science. (2020) 370:941–50. doi: 10.1126/science.aba0864

PubMed Abstract | Crossref Full Text | Google Scholar

76. Cugurra A, Mamuladze T, Rustenhoven J, Dykstra T, Beroshvili G, Greenberg ZJ, et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science. (2021) 373:eabf7844. doi: 10.1126/science.abf7844

PubMed Abstract | Crossref Full Text | Google Scholar

77. Cai R, Pan C, Ghasemigharagoz A, Todorov MI, Förstera B, Zhao S, et al. Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull–meninges connections. Nat Neurosci. (2019) 22:317–27. doi: 10.1038/s41593-018-0301-3

PubMed Abstract | Crossref Full Text | Google Scholar

78. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. (2015) 523:337–41. doi: 10.1038/nature14432

PubMed Abstract | Crossref Full Text | Google Scholar

79. Pulous FE, Cruz-Hernández JC, Yang C, Kaya Z, Paccalet A, Wojtkiewicz G, et al. Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat Neurosci. (2022) 25:567–76. doi: 10.1038/s41593-022-01060-2

PubMed Abstract | Crossref Full Text | Google Scholar

80. Le Douarin NM, Smith J. Development of the peripheral nervous system from the neural crest. Annu Rev Cell Biol. (1988) 4:375–404. doi: 10.1146/annurev.cb.04.110188.002111

PubMed Abstract | Crossref Full Text | Google Scholar

81. Bronner ME. Formation and migration of neural crest cells in the vertebrate embryo. Histochem Cell Biol. (2012) 138:179–86. doi: 10.1007/s00418-012-0999-z

PubMed Abstract | Crossref Full Text | Google Scholar

82. Gilbert SF. (ed.). The Neural Crest. In:Developmental Biology. 6th, ed. Sunderland, MA: Sinauer Associates (2000). Available online at: https://www.ncbi.nlm.nih.gov/books/NBK10065/ (Accessed April 10, 2025).

Google Scholar

83. Le Douarin NM, Creuzet S, Couly G, Dupin E. Neural crest cell plasticity and its limits. Dev Camb Engl. (2004) 131:4637–50. doi: 10.1242/dev.01350

PubMed Abstract | Crossref Full Text | Google Scholar

84. Burns AJ, Le Douarin NM. Enteric nervous system development: analysis of the selective developmental potentialities of vagal and sacral neural crest cells using quail-chick chimeras. Anat Rec. (2001) 262:16–28. doi: 10.1002/1097-0185(20010101)262:1<16::AID-AR1007>;3.0.CO;2-O

PubMed Abstract | Crossref Full Text | Google Scholar

85. Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary septation. Science. (1983) 220:1059–61. doi: 10.1126/science.6844926

PubMed Abstract | Crossref Full Text | Google Scholar

86. Kirby ML, Turnage KL, Hays BM. Characterization of conotruncal malformations following ablation of ‘cardiac' neural crest. Anat Rec. (1985) 213:87–93. doi: 10.1002/ar.1092130112

PubMed Abstract | Crossref Full Text | Google Scholar

87. Bockman DE, Kirby ML. Dependence of thymus development on derivatives of the neural crest. Science. (1984) 223:498–500. doi: 10.1126/science.6606851

PubMed Abstract | Crossref Full Text | Google Scholar

88. Kirchgessner AL, Adlersberg MA, Gershon MD. Colonization of the developing pancreas by neural precursors from the bowel. Dev Dyn. (1992) 194:142–54. doi: 10.1002/aja.1001940207

PubMed Abstract | Crossref Full Text | Google Scholar

89. Kuo BR, Erickson CA. Vagal neural crest cell migratory behavior: a transition between the cranial and trunk crest. Dev Dyn. (2011) 240:2084–100. doi: 10.1002/dvdy.22715

PubMed Abstract | Crossref Full Text | Google Scholar

90. Van Velzen M, Laman JD, KleinJan A, Poot A, Osterhaus ADME, Verjans GMGM. Neuron-interacting satellite glial cells in human trigeminal ganglia have an APC phenotype. J Immunol. (2009) 183:2456–61. doi: 10.4049/jimmunol.0900890

PubMed Abstract | Crossref Full Text | Google Scholar

91. Cui JW Li Y, Yang Y, Yang HK, Dong JM, Xiao ZH, et al. Tumor immunotherapy resistance: revealing the mechanism of PD-1/PD-L1-mediated tumor immune escape. Biomed Pharmacother. (2024) 171:116203. doi: 10.1016/j.biopha.2024.116203

PubMed Abstract | Crossref Full Text | Google Scholar

92. Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci. (2012) 15:1063–7. doi: 10.1038/nn.3144

PubMed Abstract | Crossref Full Text | Google Scholar

93. Kenney MJ, Ganta CK. Autonomic nervous system and immune system interactions. Compr Physiol. (2014) 4:1177–200. doi: 10.1002/j.2040-4603.2014.tb00574.x

Crossref Full Text | Google Scholar

94. Bellocchi C, Carandina A, Montinaro B, Targetti E, Furlan L, Rodrigues GD, et al. The interplay between autonomic nervous system and inflammation across systemic autoimmune diseases. Int J Mol Sci. (2022) 23:2449. doi: 10.3390/ijms23052449

PubMed Abstract | Crossref Full Text | Google Scholar

95. Ordovas-Montanes J, Rakoff-Nahoum S, Huang S, Riol-Blanco L, Barreiro O, von Andrian UH. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. (2015) 36:578–604. doi: 10.1016/j.it.2015.08.007

PubMed Abstract | Crossref Full Text | Google Scholar

96. Slota C, Shi A, Chen G, Bevans M, Weng N-P. Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation. Brain Behav Immun. (2015) 46:168–79. doi: 10.1016/j.bbi.2015.01.015

PubMed Abstract | Crossref Full Text | Google Scholar

97. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature. (2013) 501:52–7. doi: 10.1038/nature12479

PubMed Abstract | Crossref Full Text | Google Scholar

98. Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature. (2014) 510:157–61. doi: 10.1038/nature13199

PubMed Abstract | Crossref Full Text | Google Scholar

99. Kashem SW, Riedl MS, Yao C, Honda CN, Vulchanova L, Kaplan DH. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity. (2015) 43:515–26. doi: 10.1016/j.immuni.2015.08.016

PubMed Abstract | Crossref Full Text | Google Scholar

100. Serhan N, Basso L, Sibilano R, Petitfils C, Meixiong J, Bonnart C, et al. House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation. Nat Immunol. (2019) 20:1435–43. doi: 10.1038/s41590-019-0493-z

PubMed Abstract | Crossref Full Text | Google Scholar

101. Hoeffel G, Debroas G, Roger A, Rossignol R, Gouilly J, Laprie C, et al. Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions. Nature. (2021) 594:94–9. doi: 10.1038/s41586-021-03563-7

PubMed Abstract | Crossref Full Text | Google Scholar

102. Lai NY, Musser MA, Pinho-Ribeiro FA, Baral P, Jacobson A, Ma P, et al. Gut-innervating nociceptor neurons regulate Peyer's patch microfold cells and SFB levels to mediate salmonella host defense. Cell. (2020) 180:33–49.e22. doi: 10.1016/j.cell.2019.11.014

PubMed Abstract | Crossref Full Text | Google Scholar

103. Klose CSN, Mahlakõiv T, Moeller JB, Rankin LC, Flamar AL, Kabata H, et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature. (2017) 549:282–6. doi: 10.1038/nature23676

PubMed Abstract | Crossref Full Text | Google Scholar

104. Wallrapp A, Riesenfeld SJ, Burkett PR, Abdulnour REE, Nyman J, Dionne D, et al. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature. (2017) 549:351–6. doi: 10.1038/nature24029

PubMed Abstract | Crossref Full Text | Google Scholar

105. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. (2000) 405:458–62. doi: 10.1038/35013070

PubMed Abstract | Crossref Full Text | Google Scholar

106. Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med. (2012) 209:1057–68. doi: 10.1084/jem.20120571

PubMed Abstract | Crossref Full Text | Google Scholar

107. Watkins LR, Goehler LE, Relton JK, Tartaglia N, Silbert L, Martin D, et al. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett. (1995) 183:27–31. doi: 10.1016/0304-3940(94)11105-R

PubMed Abstract | Crossref Full Text | Google Scholar

108. Banks WA, Ortiz L, Plotkin SR, Kastin AJ. Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J Pharmacol Exp Ther. (1991) 259:988–96. doi: 10.1016/S0022-3565(25)20576-6

PubMed Abstract | Crossref Full Text | Google Scholar

109. Katayama PL, Leirão IP, Kanashiro A, Luiz JPM, Cunha FQ, Navegantes LCC, et al. The carotid body detects circulating tumor necrosis factor-alpha to activate a sympathetic anti-inflammatory reflex. Brain Behav Immun. (2022) 102:370–86. doi: 10.1016/j.bbi.2022.03.014

PubMed Abstract | Crossref Full Text | Google Scholar

110. Simpson NJ, Ferguson AV. The proinflammatory cytokine tumor necrosis factor-α excites subfornical organ neurons. J Neurophysiol. (2017) 118:1532–41. doi: 10.1152/jn.00238.2017

PubMed Abstract | Crossref Full Text | Google Scholar

111. Huerta TS, Chen AC, Chaudhry S, Tynan A, Morgan T, Park K, et al. Neural representation of cytokines by vagal sensory neurons. Nat Commun. (2025) 16:3840. doi: 10.1038/s41467-025-59248-6

PubMed Abstract | Crossref Full Text | Google Scholar

112. Jin H, Li M, Jeong E, Castro-Martinez F, Zuker CS. A body–brain circuit that regulates body inflammatory responses. Nature. (2024) 630:695–703. doi: 10.1038/s41586-024-07469-y

PubMed Abstract | Crossref Full Text | Google Scholar

113. Won TH, Arifuzzaman M, Parkhurst CN, Miranda IC, Zhang B, Hu E, et al. Host metabolism balances microbial regulation of bile acid signalling. Nature. (2025) 638:216–24. doi: 10.1038/s41586-024-08379-9

PubMed Abstract | Crossref Full Text | Google Scholar

114. Mamedova E, Árting LB, Rekling JC. Bile acids induce Ca2+ signaling and membrane permeabilizations in vagal nodose ganglion neurons. Biochem Biophys Rep. (2022) 31:101288. doi: 10.1016/j.bbrep.2022.101288

PubMed Abstract | Crossref Full Text | Google Scholar

115. Calabrò S, Kankowski S, Cescon M, Gambarotta G, Raimondo S, Haastert-Talini K, et al. Impact of gut microbiota on the peripheral nervous system in physiological, regenerative and pathological conditions. Int J Mol Sci. (2023) 24:8061. doi: 10.3390/ijms24098061

PubMed Abstract | Crossref Full Text | Google Scholar

116. Jiang W, Li D, Han R, Zhang C, Jin WN, Wood K, et al. Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages. Proc Natl Acad Sci USA. (2017). doi: 10.1073/pnas.1705491114

PubMed Abstract | Crossref Full Text | Google Scholar

117. Rönnberg E, Calounova G, Pejler G. Mast cells express tyrosine hydroxylase and store dopamine in a serglycin-dependent manner. Biol Chem. (2012) 393:107–12. doi: 10.1515/BC-2011-220

PubMed Abstract | Crossref Full Text | Google Scholar

118. Niemi JP, DeFrancesco-Lisowitz A, Roldán-Hernández L, Lindborg JA, Mandell D, Zigmond RE, et al. Critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve regeneration. J Neurosci. (2013) 33:16236–48. doi: 10.1523/JNEUROSCI.3319-12.2013

PubMed Abstract | Crossref Full Text | Google Scholar

119. Gaudet AD, Popovich PG, Ramer MS. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation. (2011) 8:110. doi: 10.1186/1742-2094-8-110

PubMed Abstract | Crossref Full Text | Google Scholar

120. Wang K, Song B, Zhu Y, Dang J, Wang T, Song Y, et al. Peripheral nerve-derived CSF1 induces BMP2 expression in macrophages to promote nerve regeneration and wound healing. NPJ Regen Med. (2024) 9:35. doi: 10.1038/s41536-024-00379-7

PubMed Abstract | Crossref Full Text | Google Scholar

121. Lindborg JA, Mack M, Zigmond RE. Neutrophils are critical for myelin removal in a peripheral nerve injury model of wallerian degeneration. J Neurosci. (2017) 37:10258–77. doi: 10.1523/JNEUROSCI.2085-17.2017

PubMed Abstract | Crossref Full Text | Google Scholar

122. Zhang F, Miao Y, Liu Q, Li S, He J. Changes of pro-inflammatory and anti-inflammatory macrophages after peripheral nerve injury. RSC Adv. (2020) 10:38767–73. doi: 10.1039/D0RA06607A

PubMed Abstract | Crossref Full Text | Google Scholar

123. Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. (2014) 13:533–48. doi: 10.1038/nrd4334

PubMed Abstract | Crossref Full Text | Google Scholar

124. Tracey KJ. The inflammatory reflex. Nature. (2002) 420:853–9. doi: 10.1038/nature01321

PubMed Abstract | Crossref Full Text | Google Scholar

125. Benarroch EE. Pain-autonomic interactions: a selective review. Clin Auton Res. (2001) 11:343–9. doi: 10.1007/BF02292765

PubMed Abstract | Crossref Full Text | Google Scholar

126. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol. (2012) 8:743–54. doi: 10.1038/nrendo.2012.189

PubMed Abstract | Crossref Full Text | Google Scholar

127. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. (2014) 505:327–34. doi: 10.1038/nature12984

PubMed Abstract | Crossref Full Text | Google Scholar

128. Xu H, Li Y, Gao Y. The role of immune cells settled in the bone marrow on adult hematopoietic stem cells. Cell Mol Life Sci. (2024) 81:420. doi: 10.1007/s00018-024-05445-3

PubMed Abstract | Crossref Full Text | Google Scholar

129. Di Rosa F, Pabst R. The bone marrow: a nest for migratory memory T cells. Trends Immunol. (2005) 26:360–6. doi: 10.1016/j.it.2005.04.011

PubMed Abstract | Crossref Full Text | Google Scholar

130. Bjurholm A, Kreicbergs A, Terenius L, Goldstein M, Schultzberg M. Neuropeptide Y-, tyrosine hydroxylase- and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J Auton Nerv Syst. (1988) 25:119–25. doi: 10.1016/0165-1838(88)90016-1

PubMed Abstract | Crossref Full Text | Google Scholar

131. Bellinger DL, Lorton D, Felten SY, Felten DL. Innervation of lymphoid organs and implications in development, aging, and autoimmunity. Int J Immunopharmacol. (1992) 14:329–44. doi: 10.1016/0192-0561(92)90162-E

PubMed Abstract | Crossref Full Text | Google Scholar

132. Zhong XP, Xia WF. Regulation of bone metabolism mediated by β-adrenergic receptor and its clinical application. World J Clin Cases. (2021) 9:8967–73. doi: 10.12998/wjcc.v9.i30.8967

PubMed Abstract | Crossref Full Text | Google Scholar

133. Nishino J, Hu W, Kishtagari A, Shen B, Gao X, Blackman CM, et al. Nonselective β-adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants. Cancer Discov. (2025) 15:748–66. doi: 10.1158/2159-8290.CD-24-0719

PubMed Abstract | Crossref Full Text | Google Scholar

134. Nalini R, Roshandel E, Mohammadzadeh S, Kazemi MH, Nikoonezhad M, Jalili A, et al. The effect of beta-adrenergic stimulation in the expression of the urokinase plasminogen activator receptor in bone marrow mesenchymal stem cells. Gene Rep. (2021) 22:101017. doi: 10.1016/j.genrep.2021.101017

Crossref Full Text | Google Scholar

135. Maestroni GJ, Cosentino M, Marino F, Togni M, Conti A, Lecchini S, et al. Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp Hematol. (1998) 26:1172–7.

PubMed Abstract | Google Scholar

136. Méndez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. (2008) 452:442–7. doi: 10.1038/nature06685

PubMed Abstract | Crossref Full Text | Google Scholar

137. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. (2006) 124:407–21. doi: 10.1016/j.cell.2005.10.041

PubMed Abstract | Crossref Full Text | Google Scholar

138. Méndez-Ferrer S, Battista M, Frenette PS. Cooperation of β2 - and β3 -adrenergic receptors in hematopoietic progenitor cell mobilization. Ann N Y Acad Sci. (2010) 1192:139–44. doi: 10.1111/j.1749-6632.2010.05390.x

PubMed Abstract | Crossref Full Text | Google Scholar

139. Zipp F, Bittner S, Schafer DP. Cytokines as emerging regulators of central nervous system synapses. Immunity. (2023) 56:914–25. doi: 10.1016/j.immuni.2023.04.011

PubMed Abstract | Crossref Full Text | Google Scholar

140. Scheiermann C, Kunisaki Y, Lucas D, Chow A, Jang JE, Zhang D, et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. (2012) 37:290–301. doi: 10.1016/j.immuni.2012.05.021

PubMed Abstract | Crossref Full Text | Google Scholar

141. Gadomski S, Fielding C, García-García A, Korn C, Kapeni C, Ashraf S, et al. A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise. Cell Stem Cell. (2022) 29:528–44.e9. doi: 10.1016/j.stem.2022.02.008

PubMed Abstract | Crossref Full Text | Google Scholar

142. Sadighi Akha AA. Aging and the immune system: an overview. J Immunol Methods. (2018) 463:21–6. doi: 10.1016/j.jim.2018.08.005

PubMed Abstract | Crossref Full Text | Google Scholar

143. Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: mechanisms and role in diseases. Ageing Res Rev. (2024) 101:102540. doi: 10.1016/j.arr.2024.102540

PubMed Abstract | Crossref Full Text | Google Scholar

144. Valiathan R, Ashman M, Asthana D. Effects of ageing on the immune system: infants to elderly. Scand J Immunol. (2016) 83:255–66. doi: 10.1111/sji.12413

PubMed Abstract | Crossref Full Text | Google Scholar

145. VanGuilder HD, Bixler GV, Brucklacher RM, Farley JA, Yan H, Warrington JP, et al. Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation. (2011) 8:138. doi: 10.1186/1742-2094-8-138

PubMed Abstract | Crossref Full Text | Google Scholar

146. Clark D, Halpern B, Miclau T, Nakamura M, Kapila Y, Marcucio R. The contribution of macrophages in old mice to periodontal disease. J Dent Res. (2021) 100:1397–404. doi: 10.1177/00220345211009463

PubMed Abstract | Crossref Full Text | Google Scholar

147. Ahmadi M, Karlsen A, Mehling J, Soendenbroe C, Mackey AL, Hyldahl RD. Aging is associated with an altered macrophage response during human skeletal muscle regeneration. Exp Gerontol. (2022) 169:111974. doi: 10.1016/j.exger.2022.111974

PubMed Abstract | Crossref Full Text | Google Scholar

148. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunol Rev. (2006) 213:48–65. doi: 10.1111/j.1600-065X.2006.00441.x

PubMed Abstract | Crossref Full Text | Google Scholar

149. Barcena de. Arellano ML, Pozdniakova S, Kühl AA, Baczko I, Ladilov Y, Regitz-Zagrosek V. Sex differences in the aging human heart: decreased sirtuins, pro-inflammatory shift and reduced anti-oxidative defense. Aging. (2019) 11:1918–33. doi: 10.18632/aging.101881

PubMed Abstract | Crossref Full Text | Google Scholar

150. Wang Z, Saxena A, Yan W, Uriarte SM, Siqueira R, Li X. The impact of aging on neutrophil functions and the contribution to periodontitis. Int J Oral Sci. (2025) 17:10. doi: 10.1038/s41368-024-00332-w

PubMed Abstract | Crossref Full Text | Google Scholar

151. Nomellini V, Faunce DE, Gomez CR, Kovacs EJ. An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition. J Leukoc Biol. (2008) 83:1493–501. doi: 10.1189/jlb.1007672

PubMed Abstract | Crossref Full Text | Google Scholar

152. Inui T, Nakagawa R, Ohkura S, Habu Y, Koike Y, Motoki K. et al. Age-associated augmentation of the synthetic ligand- mediated function of mouse NK11 Ag+ T cells: their cytokine production and hepatotoxicity in vivo and in vitro. J Immunol. (2002) 169:6127–32. doi: 10.4049/jimmunol.169.11.6127

PubMed Abstract | Crossref Full Text | Google Scholar

153. Panda A, Qian F, Mohanty S, Van Duin D, Newman FK, Zhang L, et al. age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol. (2010) 184:2518–27. doi: 10.4049/jimmunol.0901022

PubMed Abstract | Crossref Full Text | Google Scholar

154. Fang M, Roscoe F, Sigal LJ. Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J Exp Med. (2010) 207:2369–81. doi: 10.1084/jem.20100282

PubMed Abstract | Crossref Full Text | Google Scholar

155. Lynch HE, Goldberg GL, Chidgey A, Van den Brink MRM, Boyd R, Sempowski GD. Thymic involution and immune reconstitution. Trends Immunol. (2009) 30:366–73. doi: 10.1016/j.it.2009.04.003

PubMed Abstract | Crossref Full Text | Google Scholar

156. Zhao J, Yang X, Auh SL, Kim KD, Tang H, Fu YX. Do adaptive immune cells suppress or activate innate immunity? Trends Immunol. (2009) 30:8–12. doi: 10.1016/j.it.2008.10.003

PubMed Abstract | Crossref Full Text | Google Scholar

157. Weinberger B, Lazuardi L, Weiskirchner I, Keller M, Neuner C, Fischer KH, et al. Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly. Hum Immunol. (2007) 68:86–90. doi: 10.1016/j.humimm.2006.10.019

PubMed Abstract | Crossref Full Text | Google Scholar

158. Nikolich-Žugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. (2008) 8:512–22. doi: 10.1038/nri2318

PubMed Abstract | Crossref Full Text | Google Scholar

159. Wagner CL, Hanumanthu VS, Talbot CC, Abraham RS, Hamm D, Gable DL, et al. Short telomere syndromes cause a primary T cell immunodeficiency. J Clin Invest. (2018) 128:5222–34. doi: 10.1172/JCI120216

PubMed Abstract | Crossref Full Text | Google Scholar

160. Li Y, Shen Y, Hohensinner P, Ju J, Wen Z, Goodman SB, et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity. (2016) 45:903–16. doi: 10.1016/j.immuni.2016.09.013

PubMed Abstract | Crossref Full Text | Google Scholar

161. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. (2005) 102:9194–9. doi: 10.1073/pnas.0503280102

PubMed Abstract | Crossref Full Text | Google Scholar

162. Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol. (2008) 180:5283–90. doi: 10.4049/jimmunol.180.8.5283

PubMed Abstract | Crossref Full Text | Google Scholar

163. Koh BI, Mohanakrishnan V, Jeong HW, Park H, Kruse K, Choi YJ, et al. Adult skull bone marrow is an expanding and resilient haematopoietic reservoir. Nature. (2024) 636:172–81. doi: 10.1038/s41586-024-08163-9

PubMed Abstract | Crossref Full Text | Google Scholar

164. Kolabas ZI, Kuemmerle LB, Perneczky R, Förstera B, Ulukaya S, Ali M, et al. Distinct molecular profiles of skull bone marrow in health and neurological disorders. Cell. (2023) 186:3706–25.e29. doi: 10.1016/j.cell.2023.07.009

PubMed Abstract | Crossref Full Text | Google Scholar

165. Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. (2013) 14:877–82. doi: 10.1016/j.jamda.2013.05.009

PubMed Abstract | Crossref Full Text | Google Scholar

166. Sirerol-Piquer MS, Perez-Villalba A, Duart-Abadia P, Belenguer G, Gómez-Pinedo U, Blasco-Chamarro L, et al. Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species. Mol Neurodegener. (2025) 20:26. doi: 10.1186/s13024-025-00816-1

PubMed Abstract | Crossref Full Text | Google Scholar

167. Shahidehpour RK, Higdon RE, Crawford NG, Neltner JH, Ighodaro ET, Patel E, et al. Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol Aging. (2021) 99:19–27. doi: 10.1016/j.neurobiolaging.2020.12.003

PubMed Abstract | Crossref Full Text | Google Scholar

168. Sobue A, Komine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, et al. Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease. Acta Neuropathol Commun. (2021) 9:1. doi: 10.1186/s40478-020-01099-x

PubMed Abstract | Crossref Full Text | Google Scholar

169. Loppi SH, Tavera-Garcia MA, Becktel DA, Maiyo BK, Johnson KE, Nguyen TVV, et al. Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke. J Cereb Blood Flow Metab. (2023) 43:1099–114. doi: 10.1177/0271678X231157298

PubMed Abstract | Crossref Full Text | Google Scholar

170. Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. (2020) 23:194–208. doi: 10.1038/s41593-019-0566-1

PubMed Abstract | Crossref Full Text | Google Scholar

171. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. (2017) 541:481–7. doi: 10.1038/nature21029

PubMed Abstract | Crossref Full Text | Google Scholar

172. Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. (2017) 46:957–67. doi: 10.1016/j.immuni.2017.06.006

PubMed Abstract | Crossref Full Text | Google Scholar

173. Yang AC, Stevens MY, Chen MB, Lee DP, Stähli D, Gate D, et al. Physiological blood–brain transport is impaired with age by a shift in transcytosis. Nature. (2020) 583:425–30. doi: 10.1038/s41586-020-2453-z

PubMed Abstract | Crossref Full Text | Google Scholar

174. Jimenez-Gutierrez GE, Martínez-Gómez LE, Martínez-Armenta C, Pineda C, Martínez-Nava GA, Lopez-Reyes A. Molecular mechanisms of inflammation in sarcopenia: diagnosis and therapeutic update. Cells. (2022) 11:2359. doi: 10.3390/cells11152359

PubMed Abstract | Crossref Full Text | Google Scholar

175. Antuña E, Cachán-Vega C, Bermejo-Millo JC, Potes Y, Caballero B, Vega-Naredo I, et al. Inflammaging: implications in sarcopenia. Int J Mol Sci. (2022) 23:15039. doi: 10.3390/ijms232315039

PubMed Abstract | Crossref Full Text | Google Scholar

176. Sartori R, Romanello V, Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun. (2021) 12:330. doi: 10.1038/s41467-020-20123-1

PubMed Abstract | Crossref Full Text | Google Scholar

177. Kurosaka M, Machida S. Interleukin-6-induced satellite cell proliferation is regulated by induction of the JAK 2/STAT 3 signalling pathway through cyclin D1 targeting. Cell Prolif. (2013) 46:365–73. doi: 10.1111/cpr.12045

PubMed Abstract | Crossref Full Text | Google Scholar

178. Sriram S, Subramanian S, Juvvuna PK, Ge X, Lokireddy S, McFarlane CD, et al. Myostatin augments muscle-specific ring finger protein-1 expression through an NF-kB independent mechanism in SMAD3 null muscle. Mol Endocrinol. (2014) 28:317–30. doi: 10.1210/me.2013-1179

PubMed Abstract | Crossref Full Text | Google Scholar

179. Moiseeva V, Cisneros A, Sica V, Deryagin O, Lai Y, Jung S, et al. Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration. Nature. (2023) 613:169–78. doi: 10.1038/s41586-022-05535-x

PubMed Abstract | Crossref Full Text | Google Scholar

180. Rheinheimer J, de Souza BM, Cardoso NS, Bauer AC, Crispim D. Current role of the NLRP3 inflammasome on obesity and insulin resistance: a systematic review. Metabolism. (2017) 74:1–9. doi: 10.1016/j.metabol.2017.06.002

PubMed Abstract | Crossref Full Text | Google Scholar

181. He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, et al. An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance. Cell Metab. (2020) 31:580–91.e5. doi: 10.1016/j.cmet.2020.01.009

PubMed Abstract | Crossref Full Text | Google Scholar

182. Liu J, Wang L, Zhong W, Cai J, Sun Y, Li S, et al. Single-cell RNA sequencing reveals peripheral immune cell senescence and inflammatory phenotypes in patients with premature ovarian failure. J Inflamm Res. (2025) 18:2699–715. doi: 10.2147/JIR.S496130

PubMed Abstract | Crossref Full Text | Google Scholar

183. Hampton RF, Jimenez-Gonzalez M, Stanley SA. Unravelling innervation of pancreatic islets. Diabetologia. (2022) 65:1069–84. doi: 10.1007/s00125-022-05691-9

PubMed Abstract | Crossref Full Text | Google Scholar

184. Miller BM, Oderberg IM, Goessling W. Hepatic nervous system in development, regeneration, and disease. Hepatol Baltim Md. (2021) 74:3513–22. doi: 10.1002/hep.32055

PubMed Abstract | Crossref Full Text | Google Scholar

185. Wu JJ, Wei Z. Advances in the study of the effects of gut microflora on microglia in Alzheimer's disease. Front Mol Neurosci. (2023) 16:1295916. doi: 10.3389/fnmol.2023.1295916

PubMed Abstract | Crossref Full Text | Google Scholar

186. Loh JS, Mak WQ, Tan LKS, Ng CX, Chan HH, Yeow SH, et al. Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther. (2024) 9:37. doi: 10.1038/s41392-024-01743-1

PubMed Abstract | Crossref Full Text | Google Scholar

187. Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun. (2021) 22:289–303. doi: 10.1038/s41435-021-00126-8

PubMed Abstract | Crossref Full Text | Google Scholar

188. Caetano-Silva ME, Shrestha A, Duff AF, Kontic D, Brewster PC, Kasperek MC, et al. Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation. Aging Cell. (2024) 23:e14190. doi: 10.1111/acel.14190

PubMed Abstract | Crossref Full Text | Google Scholar

189. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. (2017) 21:455–66.e4. doi: 10.1016/j.chom.2017.03.002

PubMed Abstract | Crossref Full Text | Google Scholar

190. Griffiths JA, Yoo BB, Thuy-Boun P, Cantu VJ, Weldon KC, Challis C, et al. Peripheral neuronal activation shapes the microbiome and alters gut physiology. Cell Rep. (2024) 43:113953. doi: 10.1016/j.celrep.2024.113953

PubMed Abstract | Crossref Full Text | Google Scholar

191. Liu Y, Wang J, Wu C. Modulation of gut microbiota and immune system by probiotics, pre-biotics, and post-biotics. Front Nutr. (2022) 8:634897. doi: 10.3389/fnut.2021.634897

PubMed Abstract | Crossref Full Text | Google Scholar

192. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. (2015) 85:296–302. doi: 10.1016/j.neuron.2014.12.032

PubMed Abstract | Crossref Full Text | Google Scholar

193. Krouwer VJD, Hekking LHP, Langelaar-Makkinje M, Regan-Klapisz E, Post JA. Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability. Vasc Cell. (2012) 4:12. doi: 10.1186/2045-824X-4-12

PubMed Abstract | Crossref Full Text | Google Scholar

194. Stamatovic SM, Johnson AM, Keep RF, Andjelkovic AV. Junctional proteins of the blood-brain barrier: new insights into function and dysfunction. Tissue Barriers. (2016) 4:e1154641. doi: 10.1080/21688370.2016.1154641

PubMed Abstract | Crossref Full Text | Google Scholar

195. Stamatovic SM, Martinez-Revollar G, Hu A, Choi J, Keep RF, Andjelkovic AV. Decline in Sirtuin-1 expression and activity plays a critical role in blood-brain barrier permeability in aging. Neurobiol Dis. (2019) 126:105–16. doi: 10.1016/j.nbd.2018.09.006

PubMed Abstract | Crossref Full Text | Google Scholar

196. Chen T, Dai SH Li X, Luo P, Zhu J, Wang YH, et al. Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia. Redox Biol. (2018) 14:229–36. doi: 10.1016/j.redox.2017.09.016

PubMed Abstract | Crossref Full Text | Google Scholar

197. Saint-Pol J, Vandenhaute E, Boucau MC, Candela P, Dehouck L, Cecchelli R, et al. Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-β peptide accumulation. J Alzheimers Dis. (2012) 30:489–503. doi: 10.3233/JAD-2012-112090

PubMed Abstract | Crossref Full Text | Google Scholar

198. Duncombe J, Lennen RJ, Jansen MA, Marshall I, Wardlaw JM, Horsburgh K. Ageing causes prominent neurovascular dysfunction associated with loss of astrocytic contacts and gliosis. Neuropathol Appl Neurobiol. (2017) 43:477–91. doi: 10.1111/nan.12375

PubMed Abstract | Crossref Full Text | Google Scholar

199. Berthiaume AA, Schmid F, Stamenkovic S, Coelho-Santos V, Nielson CD, Weber B, et al. Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure. Nat Commun. (2022) 13:5912. doi: 10.1038/s41467-022-33464-w

PubMed Abstract | Crossref Full Text | Google Scholar

200. Fyfe I. Brain waste clearance reduced by ageing. Nat Rev Neurol. (2020) 16:128–128. doi: 10.1038/s41582-020-0320-z

PubMed Abstract | Crossref Full Text | Google Scholar

201. Jiang-Xie LF, Drieu A, Kipnis J. Waste clearance shapes aging brain health. Neuron. (2025) 113:71–81. doi: 10.1016/j.neuron.2024.09.017

PubMed Abstract | Crossref Full Text | Google Scholar

202. Galea I. The blood–brain barrier in systemic infection and inflammation. Cell Mol Immunol. (2021) 18:2489–501. doi: 10.1038/s41423-021-00757-x

PubMed Abstract | Crossref Full Text | Google Scholar

203. Van Olst L, Kamermans A, Van Der Pol SMA, Rodríguez E, Hulshof LA, Van Dijk RE, et al. Age-associated systemic factors change central and peripheral immunity in adult male mice. Brain Behav Immun. (2023) 111:395–411. doi: 10.1016/j.bbi.2023.05.004

PubMed Abstract | Crossref Full Text | Google Scholar

204. Quin C, Breznik JA, Kennedy AE, DeJong EN, Andary CM, Ermolina S, et al. Monocyte-driven inflamm-aging reduces intestinal barrier function in females. Immun Ageing. (2024) 21:65. doi: 10.1186/s12979-024-00469-6

PubMed Abstract | Crossref Full Text | Google Scholar

205. Wu ML, Yang XQ, Xue L, Duan W, Du JR. Age-related cognitive decline is associated with microbiota-gut-brain axis disorders and neuroinflammation in mice. Behav Brain Res. (2021) 402:113125. doi: 10.1016/j.bbr.2021.113125

PubMed Abstract | Crossref Full Text | Google Scholar

206. Jameson KG, Kazmi SA, Ohara TE, Son C, Yu KB, Mazdeyasnan D, et al. Select microbial metabolites in the small intestinal lumen regulates vagal activity via receptor-mediated signaling. iScience. (2025) 28:111699. doi: 10.1016/j.isci.2024.111699

PubMed Abstract | Crossref Full Text | Google Scholar

207. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell. (2016) 167:1469–80.e12. doi: 10.1016/j.cell.2016.11.018

PubMed Abstract | Crossref Full Text | Google Scholar

208. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. (2008) 582:97–105. doi: 10.1016/j.febslet.2007.11.057

PubMed Abstract | Crossref Full Text | Google Scholar

209. Feng X, Wang L, Zhou R, Zhou R, Chen L, Peng H, et al. Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging. Nat Commun. (2023) 14:3208. doi: 10.1038/s41467-023-38842-6

PubMed Abstract | Crossref Full Text | Google Scholar

210. Fang B, Zheng C, Ma Y, Wu F, Cheng L, Li Y, et al. Inhibited adipogenesis and low-grade inflammation enhance adipocyte hypertrophy in aging adipose tissue. Food Nutr Health. (2024) 1:2. doi: 10.1007/s44403-024-00006-9

Crossref Full Text | Google Scholar

211. Berillo O, Schiffrin EL. Advances in understanding of the role of immune cell phenotypes in hypertension and associated vascular disease. Can J Cardiol. (2024) 40:2321–39. doi: 10.1016/j.cjca.2024.08.270

PubMed Abstract | Crossref Full Text | Google Scholar

212. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA. (2004) 101:3100–5. doi: 10.1073/pnas.0308724101

PubMed Abstract | Crossref Full Text | Google Scholar

213. Sánchez-Alegría K, Arias C. Functional consequences of brain exposure to saturated fatty acids: from energy metabolism and insulin resistance to neuronal damage. Endocrinol Diabetes Metab. (2023) 6:e386. doi: 10.1002/edm2.386

PubMed Abstract | Crossref Full Text | Google Scholar

214. Pacholko A, Iadecola C. Hypertension, neurodegeneration, and cognitive decline. Hypertension. (2024) 81:991–1007. doi: 10.1161/HYPERTENSIONAHA.123.21356

PubMed Abstract | Crossref Full Text | Google Scholar

215. Zang H, Carlström K, Arner P, Hirschberg AL. Effects of treatment with testosterone alone or in combination with estrogen on insulin sensitivity in postmenopausal women. Fertil Steril. (2006) 86:136–44. doi: 10.1016/j.fertnstert.2005.12.039

PubMed Abstract | Crossref Full Text | Google Scholar

216. Bermingham KM, Linenberg I, Hall WL, Kadé K, Franks PW, Davies R, et al. Menopause is associated with postprandial metabolism, metabolic health and lifestyle: the ZOE PREDICT study. eBioMed. (2022) 85:104303. doi: 10.1016/j.ebiom.2022.104303

PubMed Abstract | Crossref Full Text | Google Scholar

217. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. (2021) 320:C375–91. doi: 10.1152/ajpcell.00379.2020

PubMed Abstract | Crossref Full Text | Google Scholar

218. Leguisamo NM, Lehnen AM, Machado UF, Okamoto MM, Markoski MM, Pinto GH, et al. GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome. Cardiovasc Diabetol. (2012) 11:100. doi: 10.1186/1475-2840-11-100

PubMed Abstract | Crossref Full Text | Google Scholar

219. Ren H, Yan S, Zhang B, Lu TY, Arancio O, Accili D. Glut4 expression defines an insulin-sensitive hypothalamic neuronal population. Mol Metab. (2014) 3:452–9. doi: 10.1016/j.molmet.2014.04.006

PubMed Abstract | Crossref Full Text | Google Scholar

220. Ashrafi G, Wu Z, Farrell RJ, Ryan TA. GLUT4 mobilization supports energetic demands of active synapses. Neuron. (2017) 93:606–15.e3. doi: 10.1016/j.neuron.2016.12.020

PubMed Abstract | Crossref Full Text | Google Scholar

221. Huang R, Tian S, Zhang H, Zhu W, Wang S. Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro. Brain Res Bull. (2020) 156:76–85. doi: 10.1016/j.brainresbull.2020.01.006

PubMed Abstract | Crossref Full Text | Google Scholar

222. Claassen JAHR, Thijssen DHJ, Panerai RB, Faraci FM. Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation. Physiol Rev. (2021) 101:1487–559. doi: 10.1152/physrev.00022.2020

PubMed Abstract | Crossref Full Text | Google Scholar

223. Wang J, Lu Y, Carr C, Dhandapani KM, Brann DW. Senolytic therapy is neuroprotective and improves functional outcome long-term after traumatic brain injury in mice. Front Neurosci. (2023) 17:1227705. doi: 10.3389/fnins.2023.1227705

PubMed Abstract | Crossref Full Text | Google Scholar

224. Lim S, Kim TJ, Kim YJ, Kim C, Ko SB, Kim BS. Senolytic therapy for cerebral ischemia-reperfusion injury. Int J Mol Sci. (2021) 22:11967. doi: 10.3390/ijms222111967

PubMed Abstract | Crossref Full Text | Google Scholar

225. Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model. Nat Neurosci. (2019) 22:719–28. doi: 10.1038/s41593-019-0372-9

PubMed Abstract | Crossref Full Text | Google Scholar

226. Orr ME, A. Need for refined senescence biomarkers and measures of senolytics in the brain. J Alzheimers Dis. (2024) 98:411–5. doi: 10.3233/JAD-231462

PubMed Abstract | Crossref Full Text | Google Scholar

227. Lee S, Wang EY, Steinberg AB, Walton CC, Chinta SJ, Andersen JK, et al. A guide to senolytic intervention in neurodegenerative disease. Mech Ageing Dev. (2021) 200:111585. doi: 10.1016/j.mad.2021.111585

PubMed Abstract | Crossref Full Text | Google Scholar

228. Basisty N, Kale A, Jeon OH, Kuehnemann C, Payne T, Rao C, et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLOS Biol. (2020) 18:e3000599. doi: 10.1371/journal.pbio.3000599

PubMed Abstract | Crossref Full Text | Google Scholar

229. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. (2019) 179:813–27. doi: 10.1016/j.cell.2019.10.005

PubMed Abstract | Crossref Full Text | Google Scholar

230. Muzio L, Viotti A, Martino G. Microglia in neuroinflammation and neurodegeneration: from understanding to therapy. Front Neurosci. (2021) 15:742065. doi: 10.3389/fnins.2021.742065

PubMed Abstract | Crossref Full Text | Google Scholar

231. Lima IV de A, Bastos LFS, Limborço-Filho M, Fiebich BL, de Oliveira ACP. Role of prostaglandins in neuroinflammatory and neurodegenerative diseases. Mediators Inflamm. (2012) 2012:946813. doi: 10.1155/2012/946813

PubMed Abstract | Crossref Full Text | Google Scholar

232. Orsini F, De Blasio D, Zangari R, Zanier ER, De Simoni MG. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front Cell Neurosci. (2014) 8:380. doi: 10.3389/fncel.2014.00380

PubMed Abstract | Crossref Full Text | Google Scholar

233. Morteau O. Prostaglandins and inflammation: the cyclooxygenase controversy. Arch Immunol Ther Exp. (2000) 48:473–80. doi: 10.1007/978-94-015-9702-9_6

Crossref Full Text | Google Scholar

234. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology. (1996) 47:425–32. doi: 10.1212/WNL.47.2.425

PubMed Abstract | Crossref Full Text | Google Scholar

235. Sánchez-Pernaute R, Ferree A, Cooper O, Yu M, Brownell AL, Isacson O. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease. J Neuroinflammation. (2004) 1:6. doi: 10.1186/1742-2094-1-6

PubMed Abstract | Crossref Full Text | Google Scholar

236. Carpanini SM, Torvell M, Morgan BP. Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol. (2019) 10:362. doi: 10.3389/fimmu.2019.00362

PubMed Abstract | Crossref Full Text | Google Scholar

237. Joo Y, Kim HS, Woo RS, Park CH, Shin KY, Lee JP, et al. Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer's disease models. Mol Pharmacol. (2006) 69:76–84. doi: 10.1124/mol.105.015206

PubMed Abstract | Crossref Full Text | Google Scholar

238. Lucas GNC, Leitão ACC, Alencar RL, Xavier RMF, Daher EDF, Bezerra da Silva Junior G. Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs. J Bras Nefrol. (2019) 41:124–30. doi: 10.1590/2175-8239-jbn-2018-0107

PubMed Abstract | Crossref Full Text | Google Scholar

239. Tai FWD, McAlindon ME. Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clin Med Lond Engl. (2021) 21:131–4. doi: 10.7861/clinmed.2021-0039

PubMed Abstract | Crossref Full Text | Google Scholar

240. McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci. (2011) 31:6587–94. doi: 10.1523/JNEUROSCI.0529-11.2011

PubMed Abstract | Crossref Full Text | Google Scholar

241. Solmaz V, Çinar BP, Yigittürk G, Çavuşoglu T, Taşkiran D, Erbaş O. Exenatide reduces TNF-α expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats. Eur J Pharmacol. (2015) 765:482–7. doi: 10.1016/j.ejphar.2015.09.024

PubMed Abstract | Crossref Full Text | Google Scholar

242. Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J Alzheimers Dis. (2010) 19:1205–19. doi: 10.3233/JAD-2010-1314

PubMed Abstract | Crossref Full Text | Google Scholar

243. Freire BM, De Melo FM, Basso AS. Adrenergic signaling regulation of macrophage function: do we understand it yet? Immunother Adv. (2022) 2:ltac010. doi: 10.1093/immadv/ltac010

PubMed Abstract | Crossref Full Text | Google Scholar

244. Ma Q, Wang L, Liu XX, An ZG, Luo X, Zhang LL, et al. GLP-1 plays a protective role in hippocampal neuronal cells by activating cAMP-CREB-BDNF signaling pathway against CORT+HG-induced toxicity. Heliyon. (2023) 9:e18491. doi: 10.1016/j.heliyon.2023.e18491

PubMed Abstract | Crossref Full Text | Google Scholar

245. Santiago JA, Potashkin JA. Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases. Front Aging Neurosci. (2023) 15:1185671. doi: 10.3389/fnagi.2023.1185671

PubMed Abstract | Crossref Full Text | Google Scholar

246. Nguyen LAM, Simons CW, Thomas R. Nootropic foods in neurodegenerative diseases: mechanisms, challenges, and future. Transl Neurodegener. (2025) 14:17. doi: 10.1186/s40035-025-00476-7

PubMed Abstract | Crossref Full Text | Google Scholar

247. Zhang T, Liu Z, Mi Y. Editorial: nutritional interventions on age-related neurodegenerative diseases. Front Aging Neurosci. (2023) 15:1215586. doi: 10.3389/fnagi.2023.1215586

PubMed Abstract | Crossref Full Text | Google Scholar

248. Buchman AS, Boyle PA Yu L, Shah RC, Wilson RS, Bennett DA. Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology. (2012) 78:1323–9. doi: 10.1212/WNL.0b013e3182535d35

PubMed Abstract | Crossref Full Text | Google Scholar

249. Belaya I, Ivanova M, Sorvari A, Ilicic M, Loppi S, Koivisto H, et al. Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease. J Neuroinflammation. (2020) 17:271. doi: 10.1186/s12974-020-01935-w

PubMed Abstract | Crossref Full Text | Google Scholar

250. Li Z, Chen Q, Liu J, Du Y. Physical exercise ameliorates the cognitive function and attenuates the neuroinflammation of Alzheimer's disease via miR-129–5p. Dement Geriatr Cogn Disord. (2020) 49:163–9. doi: 10.1159/000507285

PubMed Abstract | Crossref Full Text | Google Scholar

251. Bürgi B, Otten UH, Ochensberger B, Rihs S, Heese K, Ehrhard PB, et al. Basophil priming by neurotrophic factors. Activation through the trk receptor. J Immunol. (1996) 157:5582–8. doi: 10.4049/jimmunol.157.12.5582

PubMed Abstract | Crossref Full Text | Google Scholar

252. Sudheer PS, Hall JE, Donev R, Read G, Rowbottom A, Williams PE. Nicotinic acetylcholine receptors on basophils and mast cells. Anaesthesia. (2006) 61:1170–4. doi: 10.1111/j.1365-2044.2006.04870.x

PubMed Abstract | Crossref Full Text | Google Scholar

253. Watson BM, Oliveria JP, Nusca GM, Smith SG, Beaudin S, Dua B, et al. Inhibition of allergen-induced basophil activation by ASM-024, a nicotinic receptor ligand. Int Arch Allergy Immunol. (2014) 165:255–64. doi: 10.1159/000370068

PubMed Abstract | Crossref Full Text | Google Scholar

254. Yoshimura-Uchiyama C, Iikura M, Yamaguchi M, Nagase H, Ishii A, Matsushima K, et al. Differential modulation of human basophil functions through prostaglandin D2 receptors DP and chemoattractant receptor-homologous molecule expressed on Th2 cells/DP2. Clin Exp Allergy. (2004) 34:1283–90. doi: 10.1111/j.1365-2222.2004.02027.x

PubMed Abstract | Crossref Full Text | Google Scholar

255. Marino F, Pinoli M, Rasini E, Martini S, Luini A, Pulze L, et al. Dopaminergic inhibition of human neutrophils is exerted through D1-like receptors and affected by bacterial infection. Immunology. (2022) 167:508–27. doi: 10.1111/imm.13550

PubMed Abstract | Crossref Full Text | Google Scholar

256. Schneider E, Machavoine F, Bricard-Rignault R, Levasseur M, Petit-Bertron AF, Gautron S, et al. Downregulation of basophil-derived IL-4 and in vivo TH2 IgE responses by serotonin and other organic cation transporter 3 ligands. J Allergy Clin Immunol. (2011) 128:864–71.e2. doi: 10.1016/j.jaci.2011.04.043

PubMed Abstract | Crossref Full Text | Google Scholar

257. Raap U, Schmid-Ott G, Bruder M, Wichmann K, Kapp A, Werfel T. The functional activity of basophil granulocytes is modulated by acute mental stress and sympathetic activation in vivo and in vitro. J Allergy Clin Immunol. (2008) 122:1227–9. doi: 10.1016/j.jaci.2008.07.031

PubMed Abstract | Crossref Full Text | Google Scholar

258. Kawasaki A, Hara T, Joh T. Inhibitory effect of γ-aminobutyric acid (GABA) on histamine release from rat basophilic leukemia RBL-2H3 cells and rat peritoneal exudate cells. Nippon Shokuhin Kagaku Kogaku Kaishi. (2014) 61:362–6. doi: 10.3136/nskkk.61.362

PubMed Abstract | Crossref Full Text | Google Scholar

259. Xiang Z, Wu F, He Z, Tan F, Hu H, Zou C, et al. D1-like dopamine receptors promote B-cell differentiation in systemic lupus erythematosus. Cell Commun Signal. (2024) 22:502. doi: 10.1186/s12964-024-01885-3

PubMed Abstract | Crossref Full Text | Google Scholar

260. Wei L, Zhang C, Chen HY, Zhang ZJ Ji ZF, Yue T, et al. Dopamine receptor DR2 expression in B cells is negatively correlated with disease activity in rheumatoid arthritis patients. Immunobiology. (2015) 220:323–30. doi: 10.1016/j.imbio.2014.10.016

PubMed Abstract | Crossref Full Text | Google Scholar

261. Prado C, Osorio-Barrios F, Falcón P, Espinoza A, Saez JJ, Yuseff MI, et al. Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity. J Neuroinflammation. (2021) 18:292. doi: 10.1186/s12974-021-02338-1

PubMed Abstract | Crossref Full Text | Google Scholar

262. Wieber K, Fleige L, Tsiami S, Reinders J, Braun J, Baraliakos X, et al. Dopamine receptor 1 expressing B cells exert a proinflammatory role in female patients with rheumatoid arthritis. Sci Rep. (2022) 12:5985. doi: 10.1038/s41598-022-09891-6

PubMed Abstract | Crossref Full Text | Google Scholar

263. Fujii T, Mashimo M, Moriwaki Y, Misawa H, Ono S, Horiguchi K, et al. Expression and function of the cholinergic system in immune cells. Front Immunol. (2017) 8:1085. doi: 10.3389/fimmu.2017.01085

PubMed Abstract | Crossref Full Text | Google Scholar

264. Koval L, Kalashnyk O, Lykhmus O, Skok M. α7 nicotinic acetylcholine receptors are involved in suppression of the antibody immune response. J Neuroimmunol. (2018) 318:8–14. doi: 10.1016/j.jneuroim.2018.01.012

PubMed Abstract | Crossref Full Text | Google Scholar

265. Kurata-Sato I, Mughrabi IT, Rana M, Gerber M, Al-Abed Y, Sherry B, et al. Vagus nerve stimulation modulates distinct acetylcholine receptors on B cells and limits the germinal center response. Sci Adv. (2024) 10:eadn3760. doi: 10.1126/sciadv.adn3760

PubMed Abstract | Crossref Full Text | Google Scholar

266. Rinaldi A, Chiaravalli AM, Mian M, Zucca E, Tibiletti MG, Capella C, et al. Serotonin receptor 3A expression in normal and neoplastic B cells. Pathobiol J Immunopathol Mol Cell Biol. (2010) 77:129–35. doi: 10.1159/000292646

PubMed Abstract | Crossref Full Text | Google Scholar

267. Iken K, Chheng S, Fargin A, Goulet AC, Kouassi E. Serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1AReceptors. Cell Immunol. (1995) 163:1–9. doi: 10.1006/cimm.1995.1092

PubMed Abstract | Crossref Full Text | Google Scholar

268. Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun. (2012) 26:195–200. doi: 10.1016/j.bbi.2011.08.001

PubMed Abstract | Crossref Full Text | Google Scholar

269. Ben-Shalom N, Sandbank E, Abramovitz L, Hezroni H, Levine T, Trachtenberg E, et al. β2-adrenergic signaling promotes higher-affinity B cells and antibodies. Brain Behav Immun. (2023) 113:66–82. doi: 10.1016/j.bbi.2023.06.020

PubMed Abstract | Crossref Full Text | Google Scholar

270. Liao Y, Fan L, Bin P, Zhu C, Chen Q, Cai Y, et al. GABA signaling enforces intestinal germinal center B cell differentiation. Proc Natl Acad Sci USA. (2022) 119:e2215921119. doi: 10.1073/pnas.2215921119

PubMed Abstract | Crossref Full Text | Google Scholar

271. Simma N, Bose T, Kahlfuß S, Mankiewicz J, Lowinus T, Lühder F, et al. NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells. Cell Commun Signal. (2014) 12:75. doi: 10.1186/PREACCEPT-1074437141283158

PubMed Abstract | Crossref Full Text | Google Scholar

272. Aguilar D, Zhu F, Millet A, Millet N, Germano P, Pisegna J, et al. Sensory neurons regulate stimulus-dependent humoral immunity in mouse models of bacterial infection and asthma. Nat Commun. (2024) 15:8914. doi: 10.1038/s41467-024-53269-3

PubMed Abstract | Crossref Full Text | Google Scholar

273. Idzko M, Panther E, Stratz C, Müller T, Bayer H, Zissel G, et al. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. (2004) 172:6011–9. doi: 10.4049/jimmunol.172.10.6011

PubMed Abstract | Crossref Full Text | Google Scholar

274. Szabo A, Gogolak P, Koncz G, Foldvari Z, Pazmandi K, Miltner N, et al. Immunomodulatory capacity of the serotonin receptor 5-HT2B in a subset of human dendritic cells. Sci Rep. (2018) 8:1765. doi: 10.1038/s41598-018-20173-y

PubMed Abstract | Crossref Full Text | Google Scholar

275. Holst K, Guseva D, Schindler S, Sixt M, Braun A, Chopra H, et al. Serotonin receptor 5-HT7 regulates morphology and migratory properties of dendritic cells. J Cell Sci. (2015) 128:2866–80. doi: 10.1242/jcs.167999

PubMed Abstract | Crossref Full Text | Google Scholar

276. Prado C, Contreras F, González H, Díaz P, Elgueta D, Barrientos M, et al. Stimulation of dopamine receptor D5 expressed on dendritic cells potentiates Th17-mediated immunity. J Immunol. (2012) 188:3062–70. doi: 10.4049/jimmunol.1103096

PubMed Abstract | Crossref Full Text | Google Scholar

277. Fuks JM, Arrighi RBG, Weidner JM, Kumar Mendu S, Jin Z, Wallin RPA, et al. GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS Pathog. (2012) 8:e1003051. doi: 10.1371/journal.ppat.1003051

PubMed Abstract | Crossref Full Text | Google Scholar

278. Guo C, You Z, Shi H, Sun Y, Du X, Palacios G, et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature. (2023) 620:200–8. doi: 10.1038/s41586-023-06299-8

PubMed Abstract | Crossref Full Text | Google Scholar

279. Kitamura H, Kobayashi M, Wakita D, Nishimura T. Neuropeptide signaling activates dendritic cell-mediated type 1 immune responses through neurokinin-2 receptor. J Immunol. (2012) 188:4200–8. doi: 10.4049/jimmunol.1102521

PubMed Abstract | Crossref Full Text | Google Scholar

280. Maestroni GJM. Dendritic cell migration controlled by α1b-adrenergic receptors. J Immunol. (2000) 165:6743–7. doi: 10.4049/jimmunol.165.12.6743

PubMed Abstract | Crossref Full Text | Google Scholar

281. Gori S, Alcain J, Vanzulli S, Moreno Ayala MA, Candolfi M, Jancic C, et al. Acetylcholine-treated murine dendritic cells promote inflammatory lung injury. PLOS ONE. (2019) 14:e0212911. doi: 10.1371/journal.pone.0212911

PubMed Abstract | Crossref Full Text | Google Scholar

282. Campbell JA, Green J, Soveg F, Abdala-Valencia H, Cook-Mills JM. Serotonin receptor regulation of eosinophil transendothelial migration. J Immunol. (2016) 196(1_Supplement):191.1. doi: 10.4049/jimmunol.196.Supp.191.1

Crossref Full Text | Google Scholar

283. Boehme SA, Lio FM, Sikora L, Pandit TS, Lavrador K, Rao SP, et al. Cutting edge: serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin. J Immunol. (2004) 173:3599–603. doi: 10.4049/jimmunol.173.6.3599

PubMed Abstract | Crossref Full Text | Google Scholar

284. Wang H, Wu J, Zhang R. Effect of neurokinin-1 receptor knockdown on the expression of RANTES in allergic rhinitis. Am J Rhinol Allergy. (2023) 37:730–8. doi: 10.1177/19458924231191012

PubMed Abstract | Crossref Full Text | Google Scholar

285. Yocum GT, Turner DL, Danielsson J, Barajas MB, Zhang Y, Xu D, et al. GABAA receptor α4 -subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model. Am J Physiol-Lung Cell Mol Physiol. (2017) 313:L406–15. doi: 10.1152/ajplung.00107.2017

PubMed Abstract | Crossref Full Text | Google Scholar

286. Odemuyiwa SO, Lam V, Benn M, Ghahary A, Duszyk M, Moqbel R. Human peripheral blood eosinophils express functional glutamate receptors. J Allergy Clin Immunol. (2006) 117:S188–9. doi: 10.1016/j.jaci.2005.12.748

Crossref Full Text | Google Scholar

287. Liu J, Huang S, Li F, Wu M, He J, Xue Y, et al. Sympathetic nerves positively regulate eosinophil-driven allergic conjunctivitis via α1-adrenergic receptor signaling. Am J Pathol. (2020) 190:1298–308. doi: 10.1016/j.ajpath.2020.02.004

PubMed Abstract | Crossref Full Text | Google Scholar

288. Blanchet MR, Langlois A, Israël-Assayag E, Beaulieu MJ, Ferland C, Laviolette M, et al. Modulation of eosinophil activation in vitro by a nicotinic receptor agonist. J Leukoc Biol. (2007) 81:1245–51. doi: 10.1189/jlb.0906548

PubMed Abstract | Crossref Full Text | Google Scholar

289. Ertle CM, Rommel FR, Tumala S, Moriwaki Y, Klein J, Kruse J, et al. New pathways for the skin's stress response: the cholinergic neuropeptide SLURP-1 can activate mast cells and alter cytokine production in mice. Front Immunol. (2021) 12:631881. doi: 10.3389/fimmu.2021.631881

PubMed Abstract | Crossref Full Text | Google Scholar

290. Kageyama-Yahara N, Suehiro Y, Yamamoto T, Kadowaki M. IgE-induced degranulation of mucosal mast cells is negatively regulated via nicotinic acetylcholine receptors. Biochem Biophys Res Commun. (2008) 377:321–5. doi: 10.1016/j.bbrc.2008.10.004

PubMed Abstract | Crossref Full Text | Google Scholar

291. Xu H, Shi X, Li X, Zou J, Zhou C, Liu W, et al. Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review. J Neuroinflammation. (2020) 17:356. doi: 10.1186/s12974-020-02029-3

PubMed Abstract | Crossref Full Text | Google Scholar

292. Mori T, Kabashima K, Fukamachi S, Kuroda E, Sakabe J-I, Kobayashi M, et al. D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells. J Dermatol Sci. (2013) 71:37–44. doi: 10.1016/j.jdermsci.2013.03.008

PubMed Abstract | Crossref Full Text | Google Scholar

293. Wang B, Li X, Li M, Geng Y, Wang N, Jin Y, et al. Dopamine D3 receptor signaling alleviates mouse rheumatoid arthritis by promoting Toll-like receptor 4 degradation in mast cells. Cell Death Dis. (2022) 13:240. doi: 10.1038/s41419-022-04695-y

PubMed Abstract | Crossref Full Text | Google Scholar

294. Schulman ES, Davidson HC, Nishi H, Jameson BA. Cultivated human lung mast cells express multiple serotonin receptors. J Allergy Clin Immunol. (2005) 115:S187. doi: 10.1016/j.jaci.2004.12.758

Crossref Full Text | Google Scholar

295. Kushnir-Sukhov NM, Gilfillan AM, Coleman JW, Toth M, Bruening S, Metcalfe DD. Serotonin induces mast cell adhesion and chemotaxis through the 5-HT1A receptor. J Allergy Clin Immunol. (2006) 117:S67. doi: 10.1016/j.jaci.2005.12.268

PubMed Abstract | Crossref Full Text | Google Scholar

296. Le DD, Schmit D, Heck S, Omlor AJ, Sester M, Herr C, et al. Increase of mast cell-nerve association and neuropeptide receptor expression on mast cells in perennial allergic rhinitis. Neuroimmunomodulation. (2016) 23:261–70. doi: 10.1159/000453068

PubMed Abstract | Crossref Full Text | Google Scholar

297. Lauritano D, Mastrangelo F, D'Ovidio C, Ronconi G, Caraffa A, Gallenga CE, et al. Activation of mast cells by neuropeptides: the role of pro-inflammatory and anti-inflammatory cytokines. Int J Mol Sci. (2023) 24:4811. doi: 10.3390/ijms24054811

PubMed Abstract | Crossref Full Text | Google Scholar

298. Zhang YR, Keshari S, Kurihara K, Liu J, McKendrick LM, Chen CS, et al. Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation. Sci Transl Med. (2024) 16:eadq9133. doi: 10.1126/scitranslmed.adq9133

PubMed Abstract | Crossref Full Text | Google Scholar

299. Gebhardt T, Gerhard R, Bedoui S, Erpenbeck VJ, Hoffmann MW, Manns MP, et al. β2-adrenoceptor-mediated suppression of human intestinal mast cell functions is caused by disruption of filamentous actin dynamics. Eur J Immunol. (2005) 35:1124–32. doi: 10.1002/eji.200425869

PubMed Abstract | Crossref Full Text | Google Scholar

300. Cho CH, Ogle CW. Cholinergic-mediated gastric mast cell degranulation with subsequent histamine H1- and H2-receptor activation in stress ulceration in rats. Eur J Pharmacol. (1979) 55:23–33. doi: 10.1016/0014-2999(79)90144-4

PubMed Abstract | Crossref Full Text | Google Scholar

301. Nolan RA, Muir R, Runner K, Haddad EK, Gaskill PJ. Role of macrophage dopamine receptors in mediating cytokine production: implications for neuroinflammation in the context of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol. (2019) 14:134–56. doi: 10.1007/s11481-018-9825-2

PubMed Abstract | Crossref Full Text | Google Scholar

302. Meng L, Wang M, Gao Y, Chen L, Wang K, Gao W, et al. Dopamine D1 receptor agonist alleviates acute lung injury via modulating inflammatory responses in macrophages and barrier function in airway epithelial cells. Free Radic Biol Med. (2023) 202:2–16. doi: 10.1016/j.freeradbiomed.2023.03.016

PubMed Abstract | Crossref Full Text | Google Scholar

303. Qing J, Ren Y, Zhang Y, Yan M, Zhang H, Wu D, et al. Dopamine receptor D2 antagonism normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis. J Hepatol. (2022) 76:394–406. doi: 10.1016/j.jhep.2021.09.032

PubMed Abstract | Crossref Full Text | Google Scholar

304. Gaskill PJ, Calderon TM, Coley JS, Berman JW. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND. J Neuroimmune Pharmacol. (2013) 8:621–42. doi: 10.1007/s11481-013-9443-y

PubMed Abstract | Crossref Full Text | Google Scholar

305. Gomez F, Ruiz P, Briceño F, Rivera C, Lopez R. Macrophage Fcγ receptors expression is altered by treatment with dopaminergic drugs. Clin Immunol. (1999) 90:375–87. doi: 10.1006/clim.1998.4665

PubMed Abstract | Crossref Full Text | Google Scholar

306. Nieto C, Rayo I, De Las Casas-Engel M, Izquierdo E, Alonso B, Béchade C, et al. Serotonin (5-HT) shapes the macrophage gene profile through the 5-HT2B–dependent activation of the Aryl hydrocarbon receptor. J Immunol. (2020) 204:2808–17. doi: 10.4049/jimmunol.1901531

PubMed Abstract | Crossref Full Text | Google Scholar

307. Sternberg EM, Wedner HJ, Leung MK, Parker CW. Effect of serotonin (5-HT) and other monoamines on murine macrophages: modulation of interferon-gamma induced phagocytosis. J Immunol. (1987) 138:4360–5. doi: 10.4049/jimmunol.138.12.4360

Crossref Full Text | Google Scholar

308. Ruiz-Rodríguez VM, Torres-González CA, Salas-Canedo KM, Pecina-Maza NQ, Martínez-Leija ME, Portales-Pérez DP, et al. Dynamical changes in the expression of GABAergic and purinergic components occur during the polarization of THP-1 monocytes to proinflammatory macrophages. Biochem Biophys Rep. (2023) 36:101558. doi: 10.1016/j.bbrep.2023.101558

PubMed Abstract | Crossref Full Text | Google Scholar

309. Zhang B, Vogelzang A, Miyajima M, Sugiura Y, Wu Y, Chamoto K, et al. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature. (2021) 599:471–6. doi: 10.1038/s41586-021-04082-1

PubMed Abstract | Crossref Full Text | Google Scholar

310. Jang HS, Noh MR, Ha L, Kim J, Padanilam BJ. Norepinephrine-Alpha 2 adrenergic receptor axis is critical to long-term sequelae of ischemic acute kidney injury. FASEB J. (2020) 34:1–1. doi: 10.1096/fasebj.2020.34.s1.06186

Crossref Full Text | Google Scholar

311. Koda S, Zhang B, Zhou QY, Xu N, Li J, Liu JX, et al. β2-adrenergic receptor enhances the alternatively activated macrophages and promotes biliary injuries caused by helminth infection. Front Immunol. (2021) 12:754208. doi: 10.3389/fimmu.2021.754208

PubMed Abstract | Crossref Full Text | Google Scholar

312. Shanshiashvili L, Tsitsilashvili E, Dabrundashvili N, Kalandadze I, Mikeladze D. Metabotropic glutamate receptor 5 may be involved in macrophage plasticity. Biol Res. (2017) 50:4. doi: 10.1186/s40659-017-0110-2

PubMed Abstract | Crossref Full Text | Google Scholar

313. Keever KR, Cui K, Casteel JL, Singh S, Hoover DB, Williams DL, et al. Cholinergic signaling via the α7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation. J Neuroinflammation. (2024) 21:3. doi: 10.1186/s12974-023-03001-7

PubMed Abstract | Crossref Full Text | Google Scholar

314. Ganea D, Delgado M. Inhibitory neuropeptide receptors on macrophages. Microbes Infect. (2001) 3:141–7. doi: 10.1016/S1286-4579(00)01361-7

PubMed Abstract | Crossref Full Text | Google Scholar

315. Genever PG, Wilkinson DJ, Patton AJ, Peet NM, Hong Y, Mathur A, et al. Expression of a functional N-methyl-D-aspartate-type glutamate receptor by bone marrow megakaryocytes. Blood. (1999) 93:2876–83. doi: 10.1182/blood.V93.9.2876.409k31_2876_2883

Crossref Full Text | Google Scholar

316. Hearn JI, Green TN, Hisey CL, Bender M, Josefsson EC, Knowlton N, et al. Deletion of Grin1 in mouse megakaryocytes reveals NMDA receptor role in platelet function and proplatelet formation. Blood. (2022) 139:2673–90. doi: 10.1182/blood.2021014000

PubMed Abstract | Crossref Full Text | Google Scholar

317. Mo Y, Li S-Y, Liang E-Y, Lian Q-Z, Meng F-Y. The expression of functional dopamine and serotonin receptors on megakaryocytes. Blood. (2014) 124:4205. doi: 10.1182/blood.V124.21.4205.4205

Crossref Full Text | Google Scholar

318. Chen S, Hu M, Shen M, Xu Y, Wang C, Wang X, et al. Dopamine induces platelet production from megakaryocytes via oxidative stress-mediated signaling pathways. Platelets. (2018) 29:702–8. doi: 10.1080/09537104.2017.1356451

PubMed Abstract | Crossref Full Text | Google Scholar

319. Schedel A, Kaiser K, Uhlig S, Lorenz F, Sarin A, Starigk J, et al. Megakaryocytes and platelets express nicotinic acetylcholine receptors but nicotine does not affect megakaryopoiesis or platelet function. Platelets. (2016) 27:43–50. doi: 10.3109/09537104.2015.1026803

PubMed Abstract | Crossref Full Text | Google Scholar

320. Thornton S, Schedel A, Besenfelder S, Klüter H, Bugert P. Cholinergic drugs inhibit in vitro megakaryopoiesis via the alpha7-nicotinic acetylcholine receptor. Platelets. (2011) 22:390–5. doi: 10.3109/09537104.2010.551304

PubMed Abstract | Crossref Full Text | Google Scholar

321. Ye JY, Liang EY, Cheng YS, Chan GCF, Ding Y, Meng F, et al. Serotonin enhances megakaryopoiesis and proplatelet formation via p-Erk1/2 and F-actin reorganization. Stem Cells. (2014) 32:2973–82. doi: 10.1002/stem.1777

PubMed Abstract | Crossref Full Text | Google Scholar

322. Zhu F, Feng M, Sinha R, Murphy MP, Luo F, Kao KS, et al. The GABA receptor GABRR1 is expressed on and functional in hematopoietic stem cells and megakaryocyte progenitors. Proc Natl Acad Sci USA. (2019) 116:18416–22. doi: 10.1073/pnas.1906251116

PubMed Abstract | Crossref Full Text | Google Scholar

323. Shao L, Elujoba-Bridenstine A, Zink KE, Sanchez LM, Cox BJ, Pollok KE, et al. The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells. Blood. (2021) 137:775–87. doi: 10.1182/blood.2019004415

PubMed Abstract | Crossref Full Text | Google Scholar

324. Fuchs R, Stelzer I, Haas HS, Leitinger G, Schauenstein K, Sadjak A. The α1-adrenergic receptor antagonists, benoxathian and prazosin, induce apoptosis and a switch towards megakaryocytic differentiation in human erythroleukemia cells. Ann Hematol. (2009) 88:989–97. doi: 10.1007/s00277-009-0704-z

PubMed Abstract | Crossref Full Text | Google Scholar

325. Giebelen IAJ, van Westerloo DJ, LaRosa GJ, de Vos AF, van der Poll T. Stimulation of alpha 7 cholinergic receptors inhibits lipopolysaccharide-induced neutrophil recruitment by a tumor necrosis factor alpha-independent mechanism. Shock. (2007) 27:443–7. doi: 10.1097/01.shk.0000245016.78493.bb

PubMed Abstract | Crossref Full Text | Google Scholar

326. Carmona-Rivera C, Purmalek MM, Moore E, Waldman M, Walter PJ, Garraffo HM, et al. A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity. JCI Insight. (2017) 2:e89780. doi: 10.1172/jci.insight.89780

PubMed Abstract | Crossref Full Text | Google Scholar

327. Sookhai S, Wang JH, McCourt M, O'Connell D, Redmond HP. Dopamine induces neutrophil apoptosis through a dopamine D-1 receptor-independent mechanism. Surgery. (1999) 126:314–22. doi: 10.1016/S0039-6060(99)70171-6

PubMed Abstract | Crossref Full Text | Google Scholar

328. Bedoui S, Kromer A, Gebhardt T, Jacobs R, Raber K, Dimitrijevic M, et al. Neuropeptide Y receptor-specifically modulates human neutrophil function. J Neuroimmunol. (2008) 195:88–95. doi: 10.1016/j.jneuroim.2008.01.012

PubMed Abstract | Crossref Full Text | Google Scholar

329. Sun J, Ramnath RD, Bhatia M. Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils. Am J Physiol Cell Physiol. (2007) 293:C696–704. doi: 10.1152/ajpcell.00060.2007

PubMed Abstract | Crossref Full Text | Google Scholar

330. Gour N, Yong HM, Magesh A, Atakkatan A, Andrade F, Lajoie S, et al. A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection. Immunity. (2024) 57:333–48.e6. doi: 10.1016/j.immuni.2024.01.003

PubMed Abstract | Crossref Full Text | Google Scholar

331. Yang T, Liu YW, Zhao L, Wang H, Yang N, Dai SS, et al. Metabotropic glutamate receptor 5 deficiency inhibits neutrophil infiltration after traumatic brain injury in mice. Sci Rep. (2017) 7:9998. doi: 10.1038/s41598-017-10201-8

PubMed Abstract | Crossref Full Text | Google Scholar

332. Gupta R, Palchaudhuri S, Chattopadhyay D. Glutamate induces neutrophil cell migration by activating class I metabotropic glutamate receptors. Amino Acids. (2013) 44:757–67. doi: 10.1007/s00726-012-1400-1

PubMed Abstract | Crossref Full Text | Google Scholar

333. Rane MJ, Gozal D, Butt W, Gozal E, Pierce WM, Guo SZ, et al. γ-Amino butyric acid type B receptors stimulate neutrophil chemotaxis during ischemia-reperfusion. J Immunol. (2005) 174:7242–9. doi: 10.4049/jimmunol.174.11.7242

PubMed Abstract | Crossref Full Text | Google Scholar

334. Vida C, Portilla Y, Murga C. Adrenergic modulation of neutrophil and macrophage functions: pathophysiological cues. Curr Opin Physiol. (2024) 41:100780. doi: 10.1016/j.cophys.2024.100780

Crossref Full Text | Google Scholar

335. Rapalli A, Bertoni S, Arcaro V, Saccani F, Grandi A, Vivo V, et al. Dual role of endogenous serotonin in 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Front Pharmacol. (2016) 7:68doi: 10.3389/fphar.2016.00068

PubMed Abstract | Crossref Full Text | Google Scholar

336. Zanetti SR, Ziblat A, Torres NI, Zwirner NW, Bouzat C. Expression and functional role of α7 nicotinic receptor in human cytokine-stimulated natural killer (NK) cells. J Biol Chem. (2016) 291:16541–52. doi: 10.1074/jbc.M115.710574

PubMed Abstract | Crossref Full Text | Google Scholar

337. Zhao W, Huang Y, Liu Z, Cao BB, Peng YP, Qiu YH. Dopamine receptors modulate cytotoxicity of natural killer cells via cAMP-PKA-CREB signaling pathway. PLoS ONE. (2013) 8:e65860. doi: 10.1371/journal.pone.0065860

PubMed Abstract | Crossref Full Text | Google Scholar

338. Koller A, Bianchini R, Schlager S, Münz C, Kofler B, Wiesmayr S. The neuropeptide galanin modulates natural killer cell function. Neuropeptides. (2017) 64:109–15. doi: 10.1016/j.npep.2016.11.002

PubMed Abstract | Crossref Full Text | Google Scholar

339. Choi W, Ryu T, Lee J, Shim Y, Kim M, Kim H, et al. Metabotropic glutamate receptor 5 in natural killer cells attenuates liver fibrosis by exerting cytotoxicity to activated stellate cells. Hepatology. (2021) 74:2170–85. doi: 10.1002/hep.31875

PubMed Abstract | Crossref Full Text | Google Scholar

340. Bhandage AK, Friedrich LM, Kanatani S, Jakobsson-Björkén S, Escrig-Larena JI, Wagner AK, et al. GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii. J Leukoc Biol. (2021) 110:617–28. doi: 10.1002/JLB.3HI0720-431R

PubMed Abstract | Crossref Full Text | Google Scholar

341. Diaz-Salazar C, Bou-Puerto R, Mujal AM, Lau CM, Von Hoesslin M, Zehn D, et al. Cell-intrinsic adrenergic signaling controls the adaptive NK cell response to viral infection. J Exp Med. (2020) 217:e20190549. doi: 10.1084/jem.20190549

PubMed Abstract | Crossref Full Text | Google Scholar

342. Takamoto T, Hori Y, Koga Y, Toshima H, Hara A, Yokoyama MM. Norepinephrine inhibits human natural killer cell activity in vitro. Int J Neurosci. (1991) 58:127–31. doi: 10.3109/00207459108987189

PubMed Abstract | Crossref Full Text | Google Scholar

343. Benschop RJ, Schedlowski M, Wienecke H, Jacobs R, Schmidt RE. Adrenergic control of natural killer cell circulation and adhesion. Brain Behav Immun. (1997) 11:321–32. doi: 10.1006/brbi.1997.0499

PubMed Abstract | Crossref Full Text | Google Scholar

344. Hellstrand K, Hermodsson S. Serotonergic 5-HT1a receptors regulate a cell contact-mediated interaction between natural killer cells and monocytes. Scand J Immunol. (1993) 37:7–18. doi: 10.1111/j.1365-3083.1993.tb01658.x

PubMed Abstract | Crossref Full Text | Google Scholar

345. Sager G. Receptor binding sites for beta-adrenergic ligands on human erythrocytes. Biochem Pharmacol. (1982) 31:99–104. doi: 10.1016/0006-2952(82)90243-X

PubMed Abstract | Crossref Full Text | Google Scholar

346. Hagiwara H, Hollister AS, Carr RK, Inagami T. Norepinephrine and epinephrine in human erythrocyte plasma membranes. Biochem Biophys Res Commun. (1988) 154:1003–9. doi: 10.1016/0006-291X(88)90239-2

PubMed Abstract | Crossref Full Text | Google Scholar

347. Makhro A, Kaestner L, Bogdanova A. NMDA receptor activity in circulating red blood cells: methods of detection. In:Burnashev N, Szepetowski P, , editors. NMDA Receptors. New York, NY: Springer New York (2017). p. 265–82. (Methods in Molecular Biology) vol. 1677). Available online at: http://link.springer.com/10.1007/978-1-4939-7321-7_15 (Accessed June 17, 2025).

PubMed Abstract | Google Scholar

348. Makhro A. Functional NMDA Receptors in Red Blood Cells and Heart [Internet]. Unpublished) (2014). Available online at: http://rgdoi.net/10.13140/RG.2.1.3855.8486 (Accessed June 17, 2025).

Google Scholar

349. Huestis WH, McConnell HM. A functional acetylcholine receptor in the human erythrocyte. Biochem Biophys Res Commun. (1974) 57:726–32. doi: 10.1016/0006-291X(74)90606-8

PubMed Abstract | Crossref Full Text | Google Scholar

350. Bree F, Gault I. d'Athis P, Tillement JP. Beta adrenoceptors of human red blood cells, determination of their subtypes. Biochem Pharmacol. (1984) 33:4045–50. doi: 10.1016/0006-2952(84)90019-4

PubMed Abstract | Crossref Full Text | Google Scholar

351. Kim ER, Fan S, Akhmedov D, Sun K, Lim H, O'Brien W, et al. Red blood cell β-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply. JCI Insight. (2017) 2:e93367. doi: 10.1172/jci.insight.93367

PubMed Abstract | Crossref Full Text | Google Scholar

352. Trivedi G, Inoue D, Chen C, Bitner L, Chung YR, Taylor J, et al. Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors. Sci Transl Med. (2019) 11:eaaw3781. doi: 10.1126/scitranslmed.aaw3781

PubMed Abstract | Crossref Full Text | Google Scholar

353. Farooq MA, Ajmal I, Hui X, Chen Y, Ren Y, Jiang W. β2-adrenergic receptor mediated inhibition of T cell function and its implications for CAR-T cell therapy. Int J Mol Sci. (2023) 24:12837. doi: 10.3390/ijms241612837

PubMed Abstract | Crossref Full Text | Google Scholar

354. Wang XQ, Cai HH, Deng QW, Chang YZ, Peng YP, Qiu YH. Dopamine D2 receptor on CD4+ T cells is protective against inflammatory responses and signs in a mouse model of rheumatoid arthritis. Arthritis Res Ther. (2023) 25:87. doi: 10.1186/s13075-023-03071-1

PubMed Abstract | Crossref Full Text | Google Scholar

355. Contreras F, Prado C, González H, Franz D, Osorio-Barrios F, Osorio F, et al. Dopamine receptor D3 signaling on CD4+ T cells favors Th1- and Th17-mediated immunity. J Immunol. (2016) 196:4143–9. doi: 10.4049/jimmunol.1502420

PubMed Abstract | Crossref Full Text | Google Scholar

356. Osorio-Barrios F, Prado C, Contreras F, Pacheco R. Dopamine receptor D5 signaling plays a dual role in experimental autoimmune encephalomyelitis potentiating Th17-mediated immunity and favoring suppressive activity of regulatory T-cells. Front Cell Neurosci. (2018) 12:192. doi: 10.3389/fncel.2018.00192

PubMed Abstract | Crossref Full Text | Google Scholar

357. Arce-Sillas A, Sevilla-Reyes E, Álvarez-Luquín DD, Guevara-Salinas A, Boll MC, Pérez-Correa CA, et al. Expression of dopamine receptors in immune regulatory cells. Neuroimmunomodulation. (2019) 26:159–66. doi: 10.1159/000501187

PubMed Abstract | Crossref Full Text | Google Scholar

358. Nasi G, Ahmed T, Rasini E, Fenoglio D, Marino F, Filaci G, et al. Dopamine inhibits human CD8+ Treg function through D1-like dopaminergic receptors. J Neuroimmunol. (2019) 332:233–41. doi: 10.1016/j.jneuroim.2019.02.007

PubMed Abstract | Crossref Full Text | Google Scholar

359. Kipnis J, Cardon M, Avidan H, Lewitus GM, Mordechay S, Rolls A, et al. Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration. J Neurosci. (2004) 24:6133–43. doi: 10.1523/JNEUROSCI.0600-04.2004

PubMed Abstract | Crossref Full Text | Google Scholar

360. Pacheco R, Gallart T, Lluis C, Franco R. Role of glutamate on T-cell mediated immunity. J Neuroimmunol. (2007) 185:9–19. doi: 10.1016/j.jneuroim.2007.01.003

PubMed Abstract | Crossref Full Text | Google Scholar

361. Shanker A, de Aquino MTP, Hodo TD, Uzhachenko R. Glutamate receptor signaling is critical for T cell function and antitumor activity. J Immunol. (2020) 204(1 Supplement):241.42. doi: 10.4049/jimmunol.204.Supp.241.42

PubMed Abstract | Crossref Full Text | Google Scholar

362. Wu H, Herr D, MacIver NJ, Rathmell JC, Gerriets VA. CD4 T cells differentially express cellular machinery for serotonin signaling, synthesis, and metabolism. Int Immunopharmacol. (2020) 88:106922. doi: 10.1016/j.intimp.2020.106922

PubMed Abstract | Crossref Full Text | Google Scholar

363. León-Ponte M, Ahern GP, O'Connell PJ. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood. (2007) 109:3139–46. doi: 10.1182/blood-2006-10-052787

PubMed Abstract | Crossref Full Text | Google Scholar

364. Morelli AE, Sumpter TL, Rojas-Canales DM, Bandyopadhyay M, Chen Z, Tkacheva O, et al. Neurokinin-1 receptor signaling is required for efficient Ca2+ flux in T-cell-receptor-activated T cells. Cell Rep. (2020) 30:3448–65.e8. doi: 10.1016/j.celrep.2020.02.054

PubMed Abstract | Crossref Full Text | Google Scholar

365. Abad C, Jayaram B, Becquet L, Wang Y, O'Dorisio MS, Waschek JA, et al. VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage. J Neuroinflammation. (2016) 13:169. doi: 10.1186/s12974-016-0626-3

PubMed Abstract | Crossref Full Text | Google Scholar

366. Razani-Boroujerdi S, Boyd RT, Dávila-García MI, Nandi JS, Mishra NC, Singh SP, et al. T cells express α7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response. J Immunol. (2007) 179:2889–98. doi: 10.4049/jimmunol.179.5.2889

PubMed Abstract | Crossref Full Text | Google Scholar

367. Sparrow EL, James S, Hussain K, Beers SA, Cragg MS, Bogdanov YD. Activation of GABA(A) receptors inhibits T cell proliferation. PLOS ONE. (2021) 16:e0251632. doi: 10.1371/journal.pone.0251632

PubMed Abstract | Crossref Full Text | Google Scholar

Keywords: aging, neuroimmune crosstalk, immunosenescence, neurological decline, neurodegeneration

Citation: Yeo XY, Choi Y, Hong Y, Kwon HN and Jung S (2025) Contemporary insights into neuroimmune interactions across development and aging. Front. Neurol. 16:1611124. doi: 10.3389/fneur.2025.1611124

Received: 13 April 2025; Accepted: 02 July 2025;
Published: 25 July 2025.

Edited by:

William Garrow Kerr, Upstate Medical University, United States

Reviewed by:

Susana Monteiro, University of Minho, Portugal
Pedro L. Katayama, Universidade Estadual Paulista, Brazil

Copyright © 2025 Yeo, Choi, Hong, Kwon and Jung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sangyong Jung, anVuZ3N5MDUwNUBjaGEuYWMua3I=

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