Front. Immunol. Frontiers in Immunology Front. Immunol. 1664-3224 Frontiers Media S.A. 10.3389/fimmu.2025.1640110 Review Glial-mediated immune modulation in glaucomatous neurodegeneration: mechanisms and therapeutic implications ZongFangwei 1 Writing – original draft YouJiaxin 1 Writing – original draft WuHong 1 * Writing – original draft Writing – review & editing WangXuerui 2 * Writing – original draft Writing – review & editing Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin, China Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, Jilin, China Correspondence: Xuerui Wang, wangxuerui1314@jlu.edu.cn; Hong Wu, wu_hong@jlu.edu.cn 02 12 2025 2025 16 1640110 03 06 2025 13 11 2025 05 11 2025 Copyright © 2025 Zong, You, Wu and Wang. 2025 Zong, You, Wu and Wang https://creativecommons.org/licenses/by/4.0/ 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.

Glaucoma, a leading cause of irreversible blindness, is characterized by retinal ganglion cell (RGC) degeneration and optic nerve damage. While elevated intraocular pressure (IOP) is a major risk factor, emerging evidence highlights neuroinflammation as a critical driver of disease progression. Glial cells, particularly microglia, astrocytes, and Müller cells, are central to this inflammatory process, orchestrating immune responses through the release of cytokines, chemokines, and complement proteins. Microglia and astrocytes contribute to early inflammatory amplification through tumor necrosis factor-alpha (TNF-α), complement, and Toll-like receptor 4 (TLR4) pathways, while Müller cells further promote tissue damage via ATP/P2X7R signaling and senescence-associated mechanisms. Leukocyte infiltration, triggered by glial-derived chemokines and matrix metalloproteinases (MMPs), underscores the intersection of innate and adaptive immunity in glaucoma. Importantly, preclinical studies demonstrate that targeting neuroinflammatory pathways confers RGC protection, thus modulating glial activation and immune signaling represents a promising therapeutic strategy for glaucoma, particularly in IOP-refractory cases. This review synthesizes current knowledge on the role of glial cells in initiating and perpetuating immune responses that exacerbate RGC loss, and details how activated microglia and astrocytes release pro-inflammatory mediators and upregulate pathogenic signaling pathways.

 glaucoma neuroinflammation microglia astrocytes Müller cells TNF-α complement TLR4 The author(s) declare that no financial support was received for the research, and/or publication of this article. section-at-acceptance Systems Immunology Introduction

Glaucoma, a progressive optic neuropathy, involves retinal ganglion cell (RGC) apoptosis and axonal degeneration (1). Its pathogenesis is multifactorial, driven by elevated intraocular pressure (IOP), aging, oxidative stress, and genetic predisposition, yet mounting evidence identifies neuroinflammation and immune dysregulation as pivotal contributors to disease progression (2, 3). The lamina cribrosa, the principal site of injury, exhibits marked glial activation and inflammatory remodeling in both human and experimental models, where inhibition of glial activation and cytokine signaling preserves RGC integrity and optic nerve structure (4, 5). Clinically, optic disc hemorrhages and peripapillary chorioretinal atrophy may reflect secondary manifestations of glia-driven neuroinflammation (6, 7).

Studies have shown that activation of resident glial cells in the retina, including microglia, astrocytes, and Müller cells, and infiltration of peripheral immune cells such as T lymphocytes, B lymphocytes, and regulatory T cells (Tregs), play pathogenic roles and are closely associated with RGC loss (8–10). Activated microglia release tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and complement components that propagate inflammatory cascades and sensitize RGCs to injury (8, 9). Astrocytes amplify these immune responses through Toll-like receptor (TLR) activation, NF-κB signaling, and chemokine secretion, whereas Müller cells contribute to retinal immune modulation by releasing ATP, IL-6, and matrix metalloproteinases (MMPs), which facilitate leukocyte infiltration and tissue remodeling. This coordinated glia—immune axis establishes a self-perpetuating inflammatory loop that drives chronic neurodegeneration (8, 11). Notably, pharmacological modulation of these pathways demonstrates therapeutic promise. For example, rapamycin exerts neuroprotective effects not solely through inhibition of microglia activation but also by suppressing mTOR-dependent immune activation and cytokine release, underscoring the immunoregulatory dimension of glial targeting (12–14). The convergence of glial activation and immune signaling thus represents a central mechanism linking ocular hypertension to neurodegenerative pathology.

In summary, this review synthesizes current advances on how glial cells—microglia, astrocytes, and Müller cells—mediate immune modulation in glaucomatous neurodegeneration. It further highlights the molecular pathways by which glial-derived cytokines, chemokines, and complement proteins orchestrate retinal immune responses, contributing to RGC loss and optic nerve damage.

 Central nervous system immune cells and glaucoma

Glial cells in the retina and optic nerve head (ONH) are broadly classified into microglia (the resident immune cells of the central nervous system (CNS) and macroglia, which include astrocytes and Müller cells (15, 16). Microglia continuously survey the microenvironment, respond rapidly to injury, and orchestrate immune responses. In contrast, astrocytes and Müller cells maintain structural integrity, regulate extracellular ion homeostasis, and provide metabolic support to neurons (17). Under glaucomatous stress, these glial cells undergo activation and phenotypic shifts that transform them into neurotoxic effectors, contributing to progressive RGC loss (11).

Microglia

Microglia are resident immune cells within the retina that enter through the pars plana of the ciliary body and the optic nerve head (18, 19). Under physiological conditions, these cells play a crucial role in preserving retinal equilibrium by clearing cellular waste through phagocytic mechanisms (20, 21). Progressive loss of RGCs is a pathological hallmark of glaucoma, with microglia actively participating in RGC damage and immune-inflammatory responses (22). Importantly, alterations in microglial morphology and gene expression profiles emerge prior to observable RGC degeneration and measurable declines in visual function loss in glaucoma (23). As the disease advances, microglia transition into an activated state, adopting a neurodegenerative phenotype that promotes neuronal toxicity, ultimately exacerbating RGC injury and apoptosis (24, 25). Since the optic nerve constitutes a critical component of the CNS, research by Liu et al. (26) demonstrated that infrared stimulation of the CNS results in microglial activation, enhanced phagocytic activity, and release of multiple pro-inflammatory factors, including IL-1α, IL-1β, IL-6, reactive oxygen species (ROS), and TNF-α (27). Such modifications foster a pro-inflammatory CNS microenvironment that hastens RGC depletion. Retinal gap junctions (GJs) serve as vital neuroprotective structures for RGCs. In a microbead-induced ocular hypertension (OHT) murine glaucoma model, Kumar et al. (28) observed that GJ inhibition occurs concurrently with microglial activation and RGC degeneration, implying a causative relationship between microglial reactivity and RGC loss.

 Astrocytes

Astrocytes, the predominant non-neuronal glial population within the retinal nerve fiber layer, ganglion cell layer, and optic nerve, are indispensable for maintaining retinal homeostasis by restraining RGC and axonal degeneration (29). Astrocytic injury has been shown to induce degeneration of RGCs and their axons, contributing to glaucomatous vision loss (30). Additionally, deformation and remodeling of the lamina cribrosa (LC), the principal structural component of the optic nerve head, can damage both the traversing optic nerve fibers and capillaries, thus acting as a critical pathological factor in glaucoma progression (31). Disruption of astrocytic integrity precipitates RGC loss and axonal damage, thereby driving glaucomatous vision decline (32, 33), indicating that astrocytic dysfunction has direct consequences for optic nerve stability and may initiate or exacerbate glaucomatous pathology. Under pathological stress, astrocytes can undergo a phenotypic shift toward a neurotoxic, pro-inflammatory state (34). This phenotypic transition is driven by microglia-derived mediators, notably interleukin (IL)-1α, tumor necrosis factor (TNF)-α, and complement component C1q (35). Given the central role of activated microglia in glaucoma pathogenesis, microglia-driven astrocytic polarization is likely a key driver of RGC apoptosis and optic nerve injury (36). Joshi et al. (37) demonstrated that mitochondrial fragments released by microglia or in vitro preconditioning with IL-18 induces a neurotoxic astrocytic phenotype detrimental to RGC viability.

 Müller cells

Müller cells, the principal macroglial cells of the retina extending across its entire thickness, are indispensable for maintaining retinal homeostasis but exhibit profound dysfunction in glaucomatous pathology, with their presence and activation confirmed in human and experimental glaucoma models (38, 39). A hallmark of their reactive state is the upregulation of glial fibrillary acidic protein (GFAP), prominently observed in the glaucomatous optic nerve head (40). Pathological accumulation of extracellular ATP, a common feature in glaucoma, activates Müller cells via purinergic P2 receptors (P2Rs), initiating a feed-forward loop of additional ATP release. Given that RGCs express the high-threshold purinergic receptor P2X7R (32, 41), Müller cell–derived ATP can bind to RGC P2X7R, eliciting sustained calcium influx that perturbs intracellular calcium homeostasis (42, 43). This calcium overload promotes the opening of the mitochondrial permeability transition pore (mPTP), leading to mitochondrial depolarization, cytochrome c release, and the activation of calcium-dependent proteases such as calpains, ultimately culminating in caspase activation and apoptotic RGC death (44, 45). Müller-derived ATP promotes RGC injury via P2X7R-mediated calcium overload and apoptosis (41, 46). Müller–microglia crosstalk further amplifies retinal inflammation. In chronic ocular hypertension models, reactive Müller cells activate microglia through ATP/P2X7R signaling, stimulating the production of pro-inflammatory cytokines such as TNF-α and IL-6 (8). These cytokines, in turn, act on Müller cells to intensify inflammatory responses, with NF-κB signaling serving as a central mediator (47). The anti-inflammatory SIX1 gene is downregulated in glaucomatous Müller cells (48), suggesting its loss potentiates inflammatory cascades. Age-related mechanisms further link Müller cells to glaucoma. Epidemiological data associate glaucoma prevalence with aging (49), while the glaucoma-risk gene SIX6, overexpressed in glaucomatous Müller cells and astrocytes, drives senescence via p16INK4 upregulation (50, 51). These converging inflammatory, neurotoxic, and senescence-associated pathways underscore Müller cells as central effectors in glaucoma pathogenesis, irrespective of whether the initiating insult arises from RGCs, the optic nerve, or systemic aging processes (52, 53). Notably, glial cells operate not in isolation but through dynamic crosstalk. These interactions exemplify how glial communication drives a feed-forward neuroinflammatory circuit that accelerates RGC injury and optic nerve damage (54, 55). Recognizing this network-level integration is key to identifying therapeutic strategies that target glial synergy rather than isolated cell types.

 Mechanistic role of glial cells in glaucoma pathogenesis Activation of astrocytes, microglia, and Müller cells

Astrocytes and microglia, the principal glial cell populations within the retina and ONH, undergo rapid activation during the earliest stages of glaucomatous pathology (56, 57). Astrocytes, concentrated within the retinal nerve fiber layer and ganglion cell layer, are especially abundant at the lamina cribrosa, where they provide essential structural and metabolic support for RCGs (58). However, it remains debated whether glial activation serves as an initiating insult or a downstream effector in glaucoma pathogenesis. Evidence suggests that glial reactivity is not sufficient by itself to induce glaucomatous neurodegeneration, as substantial glial activation is also observed in certain ocular inflammatory models without subsequent RGC loss or optic nerve damage. Instead, elevated IOP and aging—both established glaucoma risk factors—appear to be critical upstream modulators that sensitize glial cells toward a pathogenic phenotype (11, 59). Notably, prior to detectable RGC axon damage, the expression of genes and proteins related to astrocytic activation, including pattern recognition receptor (PRR)–associated adaptor proteins and effector molecules, is markedly upregulated (60, 61). This includes enhanced complement deposition, epidermal growth factor receptor (EGFR) expression, and increased levels of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) (62). Activated microglia similarly exhibit heightened expression of inflammatory cytokines, complement components, and major histocompatibility complex (MHC) molecules (63), while facilitating the recruitment of circulating immune cells into the ONH, thereby amplifying neuroinflammatory cascades (64). Müller cells, which span the entire retinal thickness, are also activated in response to intraocular pressure elevation and neurodegenerative stress, contributing to the early pro-inflammatory milieu through ATP release and P2X7R signaling cascades. Their activation promotes microglial reactivity and amplifies retinal inflammation via NF-κB–dependent pathways (8). Neuroinflammation driven by glial cells activation in the glaucomatous ONH may lower neuronal stress thresholds and promote neuronal injury (65, 66), culminating in glial scar formation and inhibition of RGC axonal regeneration (50). Although transient or moderate glial activation can confer neuroprotection, through trophic factor release and metabolic support, prolonged or excessive activation transitions these cells into chronic inflammatory phenotypes, thereby accelerating progressive neurodegeneration (67).

 Inflammatory signaling pathways activated by glial cells TLR-mediated neuroinflammatory signaling

Toll-like receptors (TLRs), a pivotal subset of pattern recognition receptors (PRRs), serve as sentinels of the innate immune system by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (54, 68). Distinct TLR family members display ligand specificity; for example, TLR3 is activated by viral double-stranded RNA, whereas TLR4 senses endogenous stress signals such as heat shock proteins (HSPs) (69, 70). In the central nervous system, microglia express the full complement of TLRs, while astrocytes selectively express TLR2, TLR3, TLR4, TLR5, and TLR9, each attuned to discrete PAMP or DAMP signatures (71, 72). In glaucomatous retina, TLR expression is markedly elevated (73). In vitro studies reveal that both HSPs and oxidative stress act as potent inducers of TLR expression, thereby amplifying the release of pro-inflammatory cytokines and immunostimulatory mediators that activate both innate and adaptive immune pathways (74, 75). Notably, tenascin-C, an endogenous ligand for TLR4, is upregulated in glaucomatous ONH and has been shown to activate TLR4 signaling in arthritis (76, 77). It is hypothesized that tenascin-C may initiate inflammation via TLR4 prior to DAMP release by injured RGCs (78, 79). TLR activation converges on two principal signaling axes. The myeloid differentiation primary response 88 (MyD88)-dependent pathway activates nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), driving transcriptional upregulation of TNF-α, IL-1, IL-6, and a spectrum of chemokines (80, 81). Alternatively, the Toll/IL-1 receptor (TIR)-domain-containing adaptor-inducing interferon-β (TRIF)-dependent pathway predominantly engages interferon regulatory factors (IRFs) (82). Caffeic acid phenethyl ester suppresses glial activation and migration, inhibits NF-κB-mediated inflammation, and protects RGCs from degeneration (12).

 TNF-α mediated neuroinflammatory signaling

TNF-α, a central pro-inflammatory cytokine in neurodegeneration, is secreted by both astrocytes and microglia, with astrocytes constituting the predominant source in the ONH (83, 84). In glaucomatous retina and ONH, TNF-α and its primary receptor TNF receptor 1 (TNF-R1) are markedly upregulated, with elevated expression detected in RGCs and their axons (85). Despite some evidence suggests that TNF-α may exert transient neuroprotective effects during the initial stages of optic nerve injury, the preponderance of experimental data implicates it in promoting RGC death through TNF-R–dependent caspase activation, mitochondrial dysfunction, and oxidative stress (86). Binding of TNF-α to TNF-R1 activates the TNF receptor-associated death domain (TRADD), the TNF receptor-associated factor (TRAF) superfamily, and various kinases, culminating in caspase-mediated apoptosis in RGCs (87, 88). Additionally, soluble TNF-α may promote CP-AMPAR (Ca2+-permeable AMPA receptor) expression in RGCs, exacerbating excitotoxicity (89, 90). TNF-α can also induce RGC death via the FasL pathway, as intraocular injection of TNF-α leads to RGC loss, which is attenuated by FasL inhibition (91). Pharmacological or genetic TNF-α inhibition mitigates microglial activation, axonal degeneration, and RGC loss (92, 93). In corneal chemical injury models, TNF-α blockade reduces monocyte infiltration into the retina and microglial activation, thereby decreasing the incidence of secondary glaucoma and RGC death (94). TNF-α also activates c-Jun N-terminal kinase (JNK), NF-κB, and extracellular signal-regulated kinase (ERK) pathways, further potentiating glia-mediated inflammation via IL-1 upregulation (95, 96) (Figure 1).

Glail activation and immune crosstalk in glaucomatous optic nerve degeneration.

Illustration depicting the pathological mechanisms of glaucoma. It shows microglia, activated astrocytes, and Müller cells producing pro-inflammatory mediators like IL-1α, IL-6, TNF-α, and ROS. These mediators contribute to retinal ganglion cell (RGC) loss and optic nerve damage through CXCR4 signaling and neurotoxic pathways. SIX1 gene downregulation and SIX6 gene upregulation are noted. Cellular signaling involves FasL, Fas, P2X7R, and ATP, leading to neurotoxic phenotypes and inflammation. The diagram highlights complex interactions between cells and molecular signals in glaucoma progression. Complement activation

Complement activation constitutes another key early inflammatory event (97). Elevated complement levels are detected in glaucomatous retinas, particularly at the ONH and inner retinal layers (98, 99). Activation of retinal astrocytes correlates with increased C1q expression in RGCs (100). In a genetic model of glaucoma, Shinozaki et al. (30) reported that elevated IOP was accompanied by retinal C1q upregulation and RGC apoptosis. RGCs can sense damage and activate C1, triggering a cascade that activates C3 and C5 and recruits immune cells to the injury site (101, 102). Importantly, the role of C3 in glaucoma appears to be context dependent, showing a duality between early neuroprotection and late-stage neurotoxicity (103). Complement factors have dual roles in glaucoma (104). C1qa is expressed in ONH microglia and RGC dendrites; its inhibition reduces dendritic and synaptic loss in glaucoma (105). Moreover, membrane attack complexes (MACs) accumulate in the ONH and RGCs, and MAC inhibition reduces RGC apoptosis (104). Recent evidence suggests that in the early phase of disease, astrocyte-derived C3 can signal through the epidermal growth factor receptor (EGFR) pathway, promoting astrocytic survival responses and metabolic support to stressed axons (106). This transient EGFR–C3 interaction may act as a compensatory mechanism, particularly under acute intraocular pressure (IOP) elevation, to preserve tissue integrity (107, 108). However, with sustained or chronic activation, persistent C3 cleavage leads to excessive production of downstream complement fragments (C3b, C5b-9) and ultimately the formation of MAC (109, 110). MAC deposition on RGC somas and axons contributes to neurodegeneration by inducing membrane pore formation and triggering inflammatory cell recruitment (111). Although Harder et al. (106) suggest that early astrocytic C3/EGFR signaling can be beneficial, other studies indicate that in chronic glaucoma, prolonged complement activity becomes detrimental. This switch depends on the timing of activation, the cellular source (astrocyte-derived C3 and microglia-driven complement cascade), and the local inflammatory milieu, which collectively determine whether complement exerts neuroprotective or neurotoxic effects (112–114). Ischemia-reperfusion increases retinal complement expression and deposition, while C3 knockout reduces optic nerve damage and increases RGC survival (115, 116). Bosco et al. (117) demonstrated that intravitreal AAV2.CR2-Crry injection reduces retinal C3d deposition and protects RGC axons and soma under chronic ocular hypertension.

 EGFR/iNOS/COX-2 pathways

EGFR expression and tyrosine phosphorylation are elevated in activated ONH astrocytes, promoting the production of iNOS, COX-2, and prostaglandins (PGs), thereby affecting RGC survival and ONH structure (118, 119). In high IOP mouse models, both neuronal nitric oxide synthase (nNOS) and iNOS are elevated in astrocytes at the ONH and retinal layers (120). Neufeld et al. (121) linked axonal damage to excessive nitric oxide (NO) production. While eNOS and nNOS are constitutively expressed in normal ONH astrocytes and vasculature, iNOS is upregulated by day 4 of elevated IOP and persists for months. Aminoguanidine, an iNOS inhibitor, significantly reduces RGC loss and may offer neuroprotection in glaucoma (122). Zhang et al. (119, 123) showed that while COX-2 is undetectable in normal ONH, it becomes detectable within 24 hours in cultured explants and peaks at 3 days. EGF induces COX-2 expression and PGE2 synthesis in astrocytes in a time-dependent manner, which is blocked by EGFR inhibitor AG1478. Downstream, ERK and p38 pathways also regulate COX-2/PGE2 production via EGFR signaling. COX-2 oxidizes arachidonic acid to produce PGs; PGD2, PGE2, and PGI2 may exert neuroprotective effects via DP1, EP2/EP4, and IP receptors, whereas PGE2 and PGF2α can induce neurotoxicity via EP1 and FP receptors (123, 124). Although substantial evidence implicates the EGFR/iNOS/COX-2 axis in glaucomatous neuroinflammation, the temporal dynamics and context-dependent roles of individual inflammatory mediators across disease stages remain incompletely understood, warranting further investigation.

 JAK/STAT-mediated inflammatory signaling

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a key regulator of glial-mediated neuroinflammation and has been increasingly implicated in glaucomatous neurodegeneration (125). Upon cytokine binding—particularly IL-6, IL-10, and interferons—glial cell–expressed receptors activate JAK kinases, leading to phosphorylation and nuclear translocation of STAT proteins, which then drive transcription of pro- or anti-inflammatory genes depending on the cellular context (126). In glaucomatous retina, STAT3 is the most prominently activated STAT protein in astrocytes and Müller cells and is responsible for upregulating genes involved in gliosis (GFAP), cellular stress responses, and cytokine amplification (IL-6, SOCS3). Notably, elevated STAT3 phosphorylation has been documented in the optic nerve head of both rodent models and human glaucoma tissues, suggesting a conserved role in glial activation and RGC injury (127, 128). Inhibition of JAK2 or STAT3 pharmacologically (with AG490 or Stattic) mitigates gliosis, preserves RGC function, and reduces optic nerve damage in experimental models of chronic ocular hypertension (127). However, the JAK/STAT pathway exhibits dual roles: transient STAT3 activation may promote glial neuroprotective programs, while sustained or excessive activation promotes gliosis and neurotoxicity (11, 126). Importantly, crosstalk with NF-κB and PI3K/AKT pathways further integrates STAT3 into a complex signaling hub that fine-tunes glial responses under stress conditions (129). Thus, therapeutic targeting of the JAK/STAT pathway requires precise temporal and cell-specific modulation to avoid disrupting beneficial glial responses.

 Leukocyte infiltration and RGC death triggered by glial activation Immune cells infiltration in glaucoma

Astrocyte-derived matrix metalloproteinases (MMPs) may degrade the basement membrane and compromise the glial lamina at the glaucomatous ONH (130). Leukocyte transendothelial migration is among the earliest detectable changes in DBA/2J glaucoma mouse models (131). In healthy optic nerves, CD163+ macrophages are sparsely distributed along axonal septa, whereas both early- and late-stage glaucoma show increased infiltration of CD163+ macrophages into the nerve bundles (132). The accumulation and activation of macrophages and microglia within the optic nerve have been documented across multiple glaucoma models and are considered pivotal contributors to early disease pathogenesis (103, 133, 134). Transcriptomic profiling by Howell and Johnson revealed early-stage upregulation of selectins, adhesion molecules, and chemokines in glaucomatous ONH, which collectively facilitate leukocyte recruitment prior to overt axonal injury. Experimental depletion of monocytes via targeted irradiation prevents optic nerve damage, whereas restoration of injury following endothelin-2 (ET-2) administration underscores the causal role of immune cell infiltration in glaucomatous neurodegeneration (135). Glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1) may facilitate monocyte trafficking to the ONH (136). In addition to macrophages, T lymphocytes have emerged as critical contributors to glaucomatous immune pathology (137). Glial cells upregulate MHC class II molecules in glaucomatous human and experimental retinas, enabling antigen presentation and promoting T-cell activation (11, 137, 138). Glia-derived chemokines such as CCL2 and CXCL10 recruit T cells to the ONH, where infiltrating T cells release IFN-γ, TNF-α, and other pro-inflammatory mediators that further activate resident glial populations. This reciprocal amplification loop—where glial cytokines attract T cells, and T cells in turn enhance glial reactivity—forms a self-sustaining inflammatory circuit that exacerbates RGC injury (120, 137). Within the CNS, TNF-α activates endothelial cells, promoting integrin-dependent leukocyte migration (139). Astrocytes, which express multiple integrin isoforms, exhibit elevated perivascular integrin expression in response to elevated IOP. This upregulation facilitates extracellular matrix (ECM)–cytoskeleton coupling and promotes cellular migration, adhesion, differentiation, and pro-inflammatory signaling (140, 141).

 RGC death triggered by glial activation

The membrane-bound form of Fas ligand (FasL) has been identified as a key effector in RGC apoptosis in glaucomatous mouse models (91). Krishnan et al. (21) found that activated microglia release TNF-α, which upregulates FasL expression on microglia in glaucomatous retinas, enhancing FasL-Fas binding to RGCs and thereby directly triggering apoptosis and exacerbating glaucoma progression. Moreover, microglial activation is associated with upregulation of the apolipoprotein E (ApoE) gene and the galectin-3 (Lgals3) gene (142). Knockout of ApoE in glaucomatous mouse models prevented RGC loss and suppressed the expression of neurodegenerative genes including Lgals3, indicating that ApoE-related microglial activation contributes to disease progression (142). The ApoE–Lgals3 signaling axis thus represents a potential therapeutic target for glaucoma. Importantly, ApoE also serves as an endogenous ligand for the microglial receptor TREM2, activating the DAP12–SYK signaling cascade that drives metabolic reprogramming, proliferation, and a disease-associated microglial (DAM) phenotype (143–145). In this context, upregulated Lgals3 reinforces the TREM2-ApoE axis, amplifying pro-inflammatory gene expression and promoting phagocytic activity that, while initially protective, becomes maladaptive and neurotoxic (146). Concurrently, these changes are associated with the downregulation of the homeostatic CX3CR1–CX3CL1 axis, which ordinarily restrains microglial overactivation (147, 148). The combined effect is a shift toward chronic microglial activation and synaptic toxicity, accelerating RGC degeneration. These intersecting pathways highlight a mechanistic bridge between ApoE-Lgals3 and canonical TREM2/CX3CR1 signaling in shaping microglial responses during glaucomatous neurodegeneration (149).

Extracellular ATP serves as a potent astrocytic activator (150, 151). At high concentrations, ATP activates purinergic receptor P2X7R, a high-threshold subtype of the P2 receptor (P2R) family, which induces pro-inflammatory responses in astrocytes (152, 153). P2X7R activation triggers the release of chemokines, cytokines, and ROS, thereby amplifying RGC injury, and also stimulates cytokine production in Müller cells (154, 155). Furthermore, chemokine signaling pathways contribute to astrocyte-mediated neurotoxicity. Enhanced CXCR4 activation in astrocytes or microglia facilitates glutamate release from astrocytes, provoking excitotoxic injury and promoting RGC degeneration and necrosis (30). In normal-tension glaucoma (NTG) mouse models, retinal astrocytes exhibit upregulation of CXCL-12, the endogenous agonist of CXCR4 (156). Collectively, these findings underscore astrocytes as both immune effectors and direct mediators of neuronal injury, positioning astrocytic activation and phenotypic modulation as central mechanisms in glaucoma pathogenesis (Table 1).

Glial cell–mediated immune mechanisms and their roles in glaucomatous neurodegeneration.

Glial cell type Activation stimuli Key immune mediators released Signaling pathways Downstream effects on retina/ONH Functional consequences
Microglia Elevated IOP, oxidative stress, RGC-derived DAMPs TNF-α, IL-1β, IL-6, C1q, C3, ROS TLR4–MyD88/NF-κB, TNF-α–FasL, CX3CR1–CX3CL1, ApoE–TREM2/Lgals3 Cytokine amplification, complement activation, MHC II upregulation, leukocyte recruitment Early RGC apoptosis, immune cell infiltration, synaptic stripping
Astrocytes Microglial cytokines (TNF-α, IL-1α), mitochondrial fragments, tenascin-C IL-6, CXCL10, TNF-α, iNOS, COX-2, C3 TLR4–NF-κB, EGFR–iNOS–COX-2, STAT3, JNK/ERK Upregulation of adhesion molecules, basement membrane degradation (via MMPs), antigen presentation (MHC II) Glial scar formation, RGC excitotoxicity, leukocyte transmigration
Müller Cells ATP, hypoxia, aging, inflammatory cytokines ATP, IL-6, MMPs, ROS P2X7R–Ca2+ overload–mPTP, NF-κB, STAT3, SIX6–p16INK4 pathway Induction of microglial reactivity, glia–glia inflammatory loops, senescence-associated inflammation RGC mitochondrial dysfunction, apoptosis, age-linked degeneration
Cross-talk Glial-glial and glial-immune cell interaction TNF-α, IL-6, CCL2, CXCL12, FasL TNF-α–TNF-R1, CXCL12–CXCR4, Fas–FasL Positive feedback loop in inflammation, glia-mediated T cell activation Sustained neuroinflammation, loss of homeostatic restraint, chronic neurodegeneration

IOP, intraocular pressure; RGC, retinal ganglion cell; ONH, optic nerve head; DAMPs, damage-associated molecular patterns; ROS, reactive oxygen species; TLR, Toll-like receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MHC, major histocompatibility complex; EGFR, epidermal growth factor receptor; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; MMPs, matrix metalloproteinases; mPTP, mitochondrial permeability transition pore.

 Conclusion

Glial activation and immune modulation are central drivers of glaucomatous neurodegeneration, operating through tightly interlinked inflammatory networks within the optic nerve head. Activated microglia, astrocytes, and Müller cells release cytokines, chemokines, complement components, and ROS which lead to RGC injury and recruit peripheral immune cells, further amplifying tissue damage. These responses are further shaped by key signaling pathways, including TLR4–NF-κB, TNF-α–FasL, complement C3/C5–MAC formation, and EGFR/iNOS/COX-2 cascades, as well as age-related senescence programs. Chronic or excessive activation transforms initially protective glial responses into maladaptive, neurotoxic states, driving progressive RGC apoptosis, lamina cribrosa remodeling, and irreversible vision loss.

Future therapeutic strategies should prioritize temporally targeted modulation of glial activation, inhibition of pathogenic inflammatory pathways, and disruption of maladaptive glia–immune interactions. Integrating longitudinal biomarker profiling with advanced imaging could enable stage-specific interventions, particularly in early glaucoma when neuroprotection is most feasible. Moreover, the convergence of neuroinflammatory mechanisms in glaucoma with other central nervous system disorders suggests that repurposing or co-developing glia-targeted agents may accelerate translational progress. Such approaches hold the potential to expand treatment paradigms beyond intraocular pressure control, offering new avenues for preserving vision.

 Author contributions

FZ: Writing – original draft. JY: Writing – original draft. HW: Writing – original draft, Writing – review & editing. XW: Writing – original draft, Writing – review & editing.

 Conflict of interest

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

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 References Wang X Sun L Han X Li Z Xing Y Chen X . The molecular mechanisms underlying retinal ganglion cell apoptosis and optic nerve regeneration in glaucoma (Review). Int J Mol Med. (2025) 55:63. doi: 10.3892/ijmm.2025.5504, PMID: 39950327 Tribble JR Hui F Quintero H El Hajji S Bell K Di Polo A . Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering. Mol Aspects Med. (2023) 92:101193. doi: 10.1016/j.mam.2023.101193, PMID: 37331129 Ishikawa M Izumi Y Sato K Sato T Zorumski CF Kunikata H . Glaucoma and microglia-induced neuroinflammation. Front Ophthalmol (Lausanne). (2023) 3:1132011. doi: 10.3389/fopht.2023.1132011, PMID: 38983051 Fekrazad S Gouravani M Hassanzadeh G Mafhoumi A Mirzad M S SV . Optical coherence tomography alteration of the choroid and lamina cribrosa in pseudoexfoliation syndrome and glaucoma. J Glaucoma. (2025) 34:507–19. doi: 10.1097/IJG.0000000000002571, PMID: 40131012 Kurysheva NI Kim VY Kim VE Plieva KM . The role of the structure of the lamina cribrosa in the diagnosis and treatment of glaucoma. Structural and circulatory changes in the lamina cribrosa with aging and elevated intraocular pressure. Vestn Oftalmol. (2025) 141:76–82. doi: 10.17116/oftalma202514101176, PMID: 40047026 Song MK Lee Y Shin JW Lee JY Hong JW Kook MS . Comparative analysis of the optic nerve microvasculature between different optic disc phenotypes of normal-tension glaucoma patients. BMC Ophthalmol. (2025) 25:152. doi: 10.1186/s12886-025-03987-z, PMID: 40140767 Huang J Luo N Ye L Cheng L Xiang Y Yang Y . Peripapillary intrachoroidal cavitation in myopic eyes with open-angle glaucoma: association with myopic fundus changes. Graefes Arch Clin Exp Ophthalmol. (2025) 263:2619–29. doi: 10.1007/s00417-025-06822-9, PMID: 40227343 Hu X Zhao GL Xu MX Zhou H Li F Miao Y . Interplay between Müller cells and microglia aggravates retinal inflammatory response in experimental glaucoma. J Neuroinflamm. (2021) 18:303. doi: 10.1186/s12974-021-02366-x, PMID: 34952606 Llorián-Salvador M de la Fuente AG McMurran CE Dashwood A Dooley J Liston A . Regulatory T cells limit age-associated retinal inflammation and neurodegeneration. Mol Neurodegener. (2024) 19:32. doi: 10.1186/s13024-024-00724-w, PMID: 38581053 Salkar A Palanivel V Basavarajappa D Mirzaei M Schulz A Yan P . Glial and immune dysregulation in glaucoma independent of retinal ganglion cell loss: a human post-mortem histopathology study. Acta Neuropathol Commun. (2025) 13:141. doi: 10.1186/s40478-025-02066-0, PMID: 40581633 Fernández-Albarral JA Ramírez AI de Hoz R Matamoros JA Salobrar-García E Elvira-Hurtado L . Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage. Front Cell Neurosci. (2024) 18:1354569. doi: 10.3389/fncel.2024.1354569, PMID: 38333055 Jia Y Jiang S Chen C Lu G Xie Y Sun X . Caffeic acid phenethyl ester attenuates nuclear factor−κB−mediated inflammatory responses in Müller cells and protects against retinal ganglion cell death. Mol Med Rep. (2019) 19:4863–71. doi: 10.3892/mmr.2019.10151, PMID: 31059064 Echevarria FD Formichella CR Sappington RM . Interleukin-6 deficiency attenuates retinal ganglion cell axonopathy and glaucoma-related vision loss. Front Neurosci. (2017) 11:318. doi: 10.3389/fnins.2017.00318, PMID: 28620279 Wang Y Fung NSK Lam W-C Lo ACYJA . mTOR signalling pathway: a potential therapeutic target for ocular neurodegenerative diseases. Antioxidants (Basel). (2022) 11:1304. doi: 10.3390/antiox11071304, PMID: 35883796 Reichenbach A Bringmann AJG . Glia of the human retina. Glia. (2020) 68:768–96. doi: 10.1002/glia.23727, PMID: 31793693 Rodrigues MF . Influence of Elevated Hydrostatic Pressure on Müller Cells Phenotype: Do Microglia-Derived Microvesicles Play a Role?Portugal: Universidade de Coimbra (2021). Chong RS Martin KR . Glial cell interactions and glaucoma. Curr Opin Ophthalmol. (2015) 26:73–7. doi: 10.1097/ICU.0000000000000125, PMID: 25490529 MacDowell Kaswan ZA Brooks AK Hurtado M Chen EY Steelman AJ McCusker RH . Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis. Brain Behav Immun. (2025) 129:839–56. doi: 10.1016/j.bbi.2025.07.017, PMID: 40712946 Pitha I Du L Nguyen TD Quigley H . IOP and glaucoma damage: The essential role of optic nerve head and retinal mechanosensors. Prog Retin Eye Res. (2024) 99:101232. doi: 10.1016/j.preteyeres.2023.101232, PMID: 38110030 Li H Li B Zheng Y . Role of microglia/macrophage polarisation in intraocular diseases (Review). Int J Mol Med. (2024) 53:45. doi: 10.3892/ijmm.2024.5446, PMID: 38551157 Krishnan A Kocab AJ Zacks DN Marshak-Rothstein A Gregory-Ksander M . A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J Neuroinflamm. (2019) 16:184. doi: 10.1186/s12974-019-1576-3, PMID: 31570110 Bourauel L Mercieca K . Retinal nerve fibre layer OCT for glaucoma diagnosis - gold standard or just a piece of the puzzle? Klin Monbl Augenheilkd. (2025) 242:726–34. doi: 10.1055/a-2501-8538, PMID: 40719089 Tan Z Guo Y Shrestha M Sun D Gregory-Ksander M Jakobs TC . Microglia depletion exacerbates retinal ganglion cell loss in a mouse model of glaucoma. Exp Eye Res. (2022) 225:109273. doi: 10.1016/j.exer.2022.109273, PMID: 36206859 Choi S Guo L Cordeiro MF . Retinal and brain microglia in multiple sclerosis and neurodegeneration. Cells. (2021) 10:1507. doi: 10.3390/cells10061507, PMID: 34203793 Zou J Yang J Chen B Jiang J Liu J Wang C . Melatonin protects against NMDA-induced retinal ganglion cell injury by regulating the microglia-TNFα-RGC p38 MAPK pathway. Int Immunopharmacol. (2023) 118:109976. doi: 10.1016/j.intimp.2023.109976, PMID: 37098655 Liu Q Huang Y Duan M Yang Q Ren B Tang F . Microglia as therapeutic target for radiation-induced brain injury. Int J Mol Sci. (2022) 23:8286. doi: 10.3390/ijms23158286, PMID: 35955439 Xu Y Li W Zhang J Gao W Zhang T Chen Q . Inhibition of P2Y6 receptor-mediated microglia phagocytosis aggravates brain injury in mice of intracerebral hemorrhage. Cell Mol Neurobiol. (2025) 45:67. doi: 10.1007/s10571-025-01573-x, PMID: 40627214 Korimerla N Wahl DR . A complementary strategy to mitigate radiation-induced cognitive decline. Cancer Res. (2021) 81:1635–6. doi: 10.1158/0008-5472.CAN-20-4277, PMID: 34003789 Petty RM Rangan RS Curry S Brooks CD Sabnis N Clark AF . Biodistribution of reconstituted high-density lipoprotein nanoparticles for targeted delivery to retinal ganglion cells. J Ocul Pharmacol Ther. (2025) 41:281–9. doi: 10.1089/jop.2024.0191, PMID: 40248840 Shinozaki Y Kashiwagi K Koizumi S . Astrocyte immune functions and glaucoma. Int J Mol Sci. (2023) 24:2747. doi: 10.3390/ijms24032747, PMID: 36769067 Tang Y Chen Y Chen D . The heterogeneity of astrocytes in glaucoma. Front Neuroanat. (2022) 16:995369. doi: 10.3389/fnana.2022.995369, PMID: 36466782 Shinozaki Y Koizumi S . Potential roles of astrocytes and Müller cells in the pathogenesis of glaucoma. J Pharmacol Sci. (2021) 145:262–7. doi: 10.1016/j.jphs.2020.12.009, PMID: 33602506 Lee EJ Park DY Han JC Kee C . Understanding glaucoma as astrocyte-driven neurodegeneration in the optic nerve head: an integrative clinicopathological perspective. Prog Retin Eye Res. (2025) 107:101379. doi: 10.1016/j.preteyeres.2025.101379, PMID: 40517945 Han X Cao X Ju Q Ge C Lin Y Shi J . Microglial TAK1 promotes neurotoxic astrocytes and cognitive impairment in LPS-induced hippocampal neuroinflammation. J Biol Chem. (2025) 301:110225. doi: 10.1016/j.jbc.2025.110225, PMID: 40349778 Liu YX Sun H Guo WY . Astrocyte polarization in glaucoma: a new opportunity. Neural Regener Res. (2022) 17:2582–8. doi: 10.4103/1673-5374.339470, PMID: 35662185 Zhu A Cui H Su W Liu C Yu X Huang Y . C3aR in astrocytes mediates post-thoracotomy pain by inducing A1 astrocytes in male rats. Biochim Biophys Acta Mol Basis Dis. (2023) 1869:166672. doi: 10.1016/j.bbadis.2023.166672, PMID: 36871753 Joshi AU Minhas PS Liddelow SA Haileselassie B Andreasson KI Dorn GW . Author Correction: Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci. (2021) 24:289. doi: 10.1038/s41593-020-00774-5, PMID: 33324000 Redruello-Guerrero P Gómez-Tomás M Rechi-Sierra T Molinero-Sicilia L Galindo-Cabello N Usategui-Martín R . Inflammatory mechanisms in the management and treatment of retinal detachment. Metabolites. (2025) 15:442. doi: 10.3390/metabo15070442, PMID: 40710541 Kelly RJ Ajani JA Kuzdzal J Zander T Van Cutsem E Piessen G . Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. (2021) 384:1191–203. doi: 10.1056/NEJMoa2032125, PMID: 33789008 Strat AN Kirschner A Yoo H Singh A Bagué T Li H . Engineering a 3D hydrogel system to study optic nerve head astrocyte morphology and behavior. Exp Eye Res. (2022) 220:109102. doi: 10.1016/j.exer.2022.109102, PMID: 35525298 Ye SS Tang Y Song JT . ATP and adenosine in the retina and retinal diseases. Front Pharmacol. (2021) 12:654445. doi: 10.3389/fphar.2021.654445, PMID: 34211393 Križaj D Ryskamp DA Tian N Tezel G Mitchell CH Slepak VZ . From mechanosensitivity to inflammatory responses: new players in the pathology of glaucoma. Curr Eye Res. (2014) 39:105–19. doi: 10.3109/02713683.2013.836541, PMID: 24144321 Wei M Zhang G Huang Z Ding X Sun Q Zhang Y . ATP-P2X(7)R-mediated microglia senescence aggravates retinal ganglion cell injury in chronic ocular hypertension. J Neuroinflamm. (2023) 20:180. doi: 10.1186/s12974-023-02855-1, PMID: 37525172 Dostál Z Zholobenko AV Přichystalová H Gottschalk B Valentová K Malli R . Quercetin protects cardiomyoblasts against hypertonic cytotoxicity by abolishing intracellular Ca(2+) elevations and mitochondrial depolarisation. Biochem Pharmacol. (2024) 222:116094. doi: 10.1016/j.bcp.2024.116094, PMID: 38423187 Xing L Venables MJ Trudeau VL . Role of aromatase and radial glial cells in neurotoxin-induced dopamine neuron degeneration and regeneration. Gen Comp Endocrinol. (2017) 241:69–79. doi: 10.1016/j.ygcen.2016.02.011, PMID: 26873632 Shigetomi E Saito K Sano F Koizumi S . Aberrant calcium signals in reactive astrocytes: A key process in neurological disorders. Int J Mol Sci. (2019) 20:996. doi: 10.3390/ijms20040996, PMID: 30823575 Liu Z Mar KB Hanners NW Perelman SS Kanchwala M Xing C . A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB. Nature. (2019) 568:249–53. doi: 10.1038/s41586-019-1041-6, PMID: 30894749 Lukowski SW Lo CY Sharov AA Nguyen Q Fang L Hung SS . A single-cell transcriptome atlas of the adult human retina. EMBO J. (2019) 38:e100811. doi: 10.15252/embj.2018100811, PMID: 31436334 Tashtitova L Aldasheva N . Study of the prevalence of glaucoma in Kazakhstan. Klin Monbl Augenheilkd. (2022) 239:202–7. doi: 10.1055/a-1327-3999, PMID: 33853192 Skowronska-Krawczyk D Zhao L Zhu J Weinreb RN Cao G Luo J . P16INK4a upregulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma. Mol Cell. (2015) 59:931–40. doi: 10.1016/j.molcel.2015.07.027, PMID: 26365380 Diacou R Zhao Y Zheng D Cvekl A Liu W . Six3 and six6 are jointly required for the maintenance of multipotent retinal progenitors through both positive and negative regulation. Cell Rep. (2018) 25:2510–2523.e4. doi: 10.1016/j.celrep.2018.10.106, PMID: 30485816 Choi S Choi SH Bastola T Kim KY Park S Weinreb RN . AIBP protects müller glial cells against oxidative stress-induced mitochondrial dysfunction and reduces retinal neuroinflammation. Antioxidants (Basel). (2024) 13:1252. doi: 10.3390/antiox13101252, PMID: 39456505 Kashihara T Morita Y Hatta M Inoue S Suzuki Y Morita A . YAP activation in Müller cells protects against NMDA-induced retinal ganglion cell injury by regulating Bcl-xL expression. Front Pharmacol. (2024) 15:1446521. doi: 10.3389/fphar.2024.1446521, PMID: 39166115 Geiduschek EK McDowell CM . The fibro-inflammatory response in the glaucomatous optic nerve head. J.I.J.O.M.S. (2023) 24:13240. doi: 10.3390/ijms241713240, PMID: 37686046 Zhao X Sun R Luo X Wang F Sun X . The interaction between microglia and macroglia in glaucoma. Front Neurosci. (2021) 15:610788. doi: 10.3389/fnins.2021.610788, PMID: 34121982 Batsuuri K Toychiev AH Viswanathan S Wohl SG Srinivas M . Targeting connexin 43 in retinal astrocytes promotes neuronal survival in glaucomatous injury. Glia. (2025) 73:1398–419. doi: 10.1002/glia.70013, PMID: 40156150 Ma B Ren J Qian X . Study on the polarization of astrocytes in the optic nerve head of rats under high intraocular pressure: in vitro. Bioengineering (Basel). (2025) 12:104. doi: 10.3390/bioengineering12020104, PMID: 40001624 Waxman S Schilpp H Linton A Jakobs TC Sigal IA . Morphological comparison of astrocytes in the lamina cribrosa and glial lamina. Invest Ophthalmol Vis Sci. (2025) 66:1. doi: 10.1167/iovs.66.3.1, PMID: 40029245 Au NPB Ma CHE . Neuroinflammation, microglia and implications for retinal ganglion cell survival and axon regeneration in traumatic optic neuropathy. Front Immunol. (2022) 13:860070. doi: 10.3389/fimmu.2022.860070, PMID: 35309305 Li P Shi X Prokosch V . Dual role of microglia in glaucoma: Regulation of neuroinflammation and neuroregeneration. Neural Regener Res. (2025). doi: 10.4103/NRR.NRR-D-24-00876, PMID: 40536999 Williams PA Marsh-Armstrong N Howell GR . Neuroinflammation in glaucoma: A new opportunity. Exp Eye Res. (2017) 157:20–7. doi: 10.1016/j.exer.2017.02.014, PMID: 28242160 Lee IT Lin HC Huang TH Tseng CN Cheng HT Huang WC . Anti-Inflammatory Effect of Resveratrol Derivatives via the Downregulation of Oxidative-Stress-Dependent and c-Src Transactivation EGFR Pathways on Rat Mesangial Cells. Antioxidants (Basel). (2022) 11:835. doi: 10.3390/antiox11050835, PMID: 35624699 Shirahama S Okunuki Y Lee MY Karg MM Refaian N Krasniqi D . Preventing the antigen-presenting function of retinal microglia blocks autoimmune neuroinflammation by dendritic cell-primed CD4(+) T cells. J Autoimmun. (2025) 153:103417. doi: 10.1016/j.jaut.2025.103417, PMID: 40239533 Çalışkan G French T Enrile Lacalle S Del Angel M Steffen J Heimesaat MM . Antibiotic-induced gut dysbiosis leads to activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus. Brain Behav Immun. (2022) 99:203–17. doi: 10.1016/j.bbi.2021.10.007, PMID: 34673174 Gaviglio EA Peralta Ramos JM Arroyo DS Bussi C Iribarren P Rodriguez-Galan MC . Systemic sterile induced-co-expression of IL-12 and IL-18 drive IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain. Int Immunopharmacol. (2022) 105:108546. doi: 10.1016/j.intimp.2022.108546, PMID: 35074570 Porte R Belloy M Audibert A Bassot E Aïda A Alis M . Protective function and differentiation cues of brain-resident CD8+ T cells during surveillance of latent Toxoplasma gondii infection. Proc Natl Acad Sci U.S.A. (2024) 121:e2403054121. doi: 10.1073/pnas.2403054121, PMID: 38838017 Wang N Sun C Yang Y Zhang D Huang L Xu C . Gut microbiota-derived indoleacetic acid attenuates neuroinflammation and neurodegeneration in glaucoma through ahr/rage pathway. J Neuroinflamm. (2025) 22:179. doi: 10.1186/s12974-025-03505-4, PMID: 40640940 Choi S Choi SH Bastola T Park Y Oh J Kim KY . AIBP: A new safeguard against glaucomatous neuroinflammation. Cells. (2024) 13:198. doi: 10.3390/cells13020198, PMID: 38275823 Zhuang S Li F Wang L Lai Z Li D Wu H . Neutrophil extracellular trap-derived double-stranded RNA aggravates PANoptosis in renal ischemia reperfusion injury. Cell Commun Signal. (2025) 23:140. doi: 10.1186/s12964-025-02145-8, PMID: 40098148 Shi Y Li J Zhong Q Chen H Ma X Hu Y . Genetic deletion of histone deacetylase 6 prevents peritoneal fibrosis via suppression of heat shock protein 90 deacetylation. J Pathol. (2025) 266:447–64. doi: 10.1002/path.6436, PMID: 40539829 Augusto-Oliveira M Tremblay M Verkhratsky A . Receptors on microglia. Adv Neurobiol. (2024) 37:83–121. doi: 10.1007/978-3-031-55529-9_6, PMID: 39207688 Fischer S Nasyrov E Brosien M Preissner KT Marti HH Kunze R . Self-extracellular RNA promotes pro-inflammatory response of astrocytes to exogenous and endogenous danger signals. J Neuroinflamm. (2021) 18:252. doi: 10.1186/s12974-021-02286-w, PMID: 34727934 Shevchenko AV Prokofiev VF Konenkov VI Chernykh VV Trunov AN . Features of toll-like receptor genes (TLR-2, TLR-3, TLR-4 and TLR-6) polymorphism in open-angle glaucoma patients. Vavilovskii Zhurnal Genet Selektsii. (2025) 29:128–34. doi: 10.18699/vjgb-25-15, PMID: 40144379 Hosseindoust A Ha S Lokhande A Mun J Kim YI Kim J . The targeted anti-Salmonella bacteriophage attenuated the inflammatory response of laying hens challenged with Salmonella Gallinarum. Poult Sci. (2023) 102:102296. doi: 10.1016/j.psj.2022.102296, PMID: 36463778 Luo C Yang X Kain AD Powell DW Kuehn MH Tezel G . Glaucomatous tissue stress and the regulation of immune response through glial Toll-like receptor signaling. Invest Ophthalmol Vis Sci. (2010) 51:5697–707. doi: 10.1167/iovs.10-5407, PMID: 20538986 Wiemann S Reinhard J Reinehr S Cibir Z Joachim SC Faissner A . Loss of the extracellular matrix molecule tenascin-C leads to absence of reactive gliosis and promotes anti-inflammatory cytokine expression in an autoimmune glaucoma mouse model. Front Immunol. (2020) 11:66279. doi: 10.3389/fimmu.2020.566279, PMID: 33162981 Hongu T Pein M Insua-Rodríguez J Gutjahr E Mattavelli G Meier J . Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs. Nat Cancer. (2022) 3:486–504. doi: 10.1038/s43018-022-00353-6, PMID: 35469015 Gong T Zhang X Liu X Ye Y Tian Z Yin S . Exosomal Tenascin-C primes macrophage pyroptosis amplifying aberrant inflammation during sepsis-induced acute lung injury. Transl Res. (2024) 270:66–80. doi: 10.1016/j.trsl.2024.04.001, PMID: 38604333 Soto I Howell GR . The complex role of neuroinflammation in glaucoma. Cold Spring Harb Perspect Med. (2014) 4:a017269. doi: 10.1101/cshperspect.a017269, PMID: 24993677 Wagner N Reinehr S Palmhof M Schuschel D Tsai T Sommer E . Microglia activation in retinal ischemia triggers cytokine and toll-like receptor response. J Mol Neurosci. (2021) 71:527–44. doi: 10.1007/s12031-020-01674-w, PMID: 32833183 Dawuti A Sun S Wang R Gong D Liu R Kong D . Salvianolic acid A alleviates heart failure with preserved ejection fraction via regulating TLR/Myd88/TRAF/NF-κB and p38MAPK/CREB signaling pathways. BioMed Pharmacother. (2023) 168:115837. doi: 10.1016/j.biopha.2023.115837, PMID: 37931518 Fathy Mohamed Y Fernandez RC . Programming Bordetella pertussis lipid A to promote adjuvanticity. Microb Cell Fact. (2024) 23:250. doi: 10.1186/s12934-024-02518-7, PMID: 39272136 Lahiri A Sims SG Herstine JA Meyer A Marshall MJ Jahan I . Endoplasmic reticulum stress amplifies cytokine responses in astrocytes via a PERK/eIF2α/JAK1 signaling axis. Glia. (2025) 73:2273–88. doi: 10.1002/glia.70067, PMID: 40685560 Thougaard E Nielsen PV Raffaele S Nielsen AN Larsen LL Corradini S . Systemic inhibition of soluble TNF significantly changes glial cell populations leading to improved myelin integrity and better functional outcome after experimental stroke. BioMed Pharmacother. (2025) 189:118334. doi: 10.1016/j.biopha.2025.118334, PMID: 40645014 Fuchs C Forster V Balse E Sahel JA Picaud S Tessier LH . Retinal-cell-conditioned medium prevents TNF-alpha-induced apoptosis of purified ganglion cells. Invest Ophthalmol Vis Sci. (2005) 46:2983–91. doi: 10.1167/iovs.04-1177, PMID: 16043875 Malpetti M Swann P Tsvetanov KA Chouliaras L Strauss A Chikaura T . Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration. Brain. (2025) 148:493–505. doi: 10.1093/brain/awae269, PMID: 39155063 Sun Z Ye J Sun W Jiang L Shan B Zhang M . Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis. Nat Commun. (2025) 16:1890. doi: 10.1038/s41467-025-57211-z, PMID: 39987261 Tian W Li Y Liu F Liu H Li C Bao L . Strychni Semen and two alkaloidal components cause apoptosis in HK-2 cells through TRADD-MAPK/NF-κB pathway. Toxicon. (2025) 256:108224. doi: 10.1016/j.toxicon.2024.108224, PMID: 39798900 Wen X Cahill AL Barta C Thoreson WB Nawy S . Elevated pressure increases ca(2+) influx through AMPA receptors in select populations of retinal ganglion cells. Front Cell Neurosci. (2018) 12:162. doi: 10.3389/fncel.2018.00162, PMID: 29950974 Cueva Vargas JL Osswald IK Unsain N Aurousseau MR Barker PA Bowie D . Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable AMPA receptor activation. J Neurosci. (2015) 35:12088–102. doi: 10.1523/JNEUROSCI.1273-15.2015, PMID: 26338321 Krishnan A Fei F Jones A Busto P Marshak-Rothstein A Ksander BR . Overexpression of soluble fas ligand following adeno-associated virus gene therapy prevents retinal ganglion cell death in chronic and acute murine models of glaucoma. J Immunol. (2016) 197:4626–38. doi: 10.4049/jimmunol.1601488, PMID: 27849168 Wang Q Dong J Du M Liu X Zhang S Zhang D . Chitosan-rapamycin carbon dots alleviate glaucomatous retinal injury by inducing autophagy to promote M2 microglial polarization. Int J Nanomedicine. (2024) 19:2265–84. doi: 10.2147/IJN.S440025, PMID: 38476273 Roh M Zhang Y Murakami Y Thanos A Lee SC Vavvas DG . Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma. PloS One. (2012) 7:e40065. doi: 10.1371/journal.pone.0040065, PMID: 22802951 Paschalis EI Lei F Zhou C Kapoulea V Thanos A Dana R . The role of microglia and peripheral monocytes in retinal damage after corneal chemical injury. Am J Pathol. (2018) 188:1580–96. doi: 10.1016/j.ajpath.2018.03.005, PMID: 29630857 Shen Y Zhang ZJ Zhu MD Jiang BC Yang T Gao YJ . Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice. Neurobiol Dis. (2015) 79:100–10. doi: 10.1016/j.nbd.2015.04.012, PMID: 25956228 Chistyakov DV Astakhova AA Goriainov SV Sergeeva MG . Comparison of PPAR ligands as modulators of resolution of inflammation, via their influence on cytokines and oxylipins release in astrocytes. Int J Mol Sci. (2020) 21:9577. doi: 10.3390/ijms21249577, PMID: 33339154 Gao J Wang W Mo Y . Retinal degenerative diseases: complement system-microglia crosstalk. Surv Ophthalmol. (2025) 9577. doi: 10.1016/j.survophthal.2025.08.005, PMID: 40774393 Chan ASY Tun SBB Lynn MN Ho C Tun TA Girard MJA . Intravitreal neuroglobin mitigates primate experimental glaucomatous structural damage in association with reduced optic nerve microglial and complement 3-astrocyte activation. Biomolecules. (2023) 13:961. doi: 10.3390/biom13060961, PMID: 37371541 Reinehr S Doerner JD Mueller-Buehl AM Koch D Fuchshofer R Dick HB . Cytokine and complement response in the glaucomatous βB1-CTGF mouse model. Front Cell Neurosci. (2021) 15:718087. doi: 10.3389/fncel.2021.718087, PMID: 34867198 Sterling JK Adetunji MO Guttha S Bargoud AR Uyhazi KE Ross AG . GLP-1 receptor agonist NLY01 reduces retinal inflammation and neuron death secondary to ocular hypertension. Cell Rep. (2020) 33:108271. doi: 10.1016/j.celrep.2020.108271, PMID: 33147455 Peterson SL Li Y Sun CJ Wong KA Leung KS de Lima S . Retinal ganglion cell axon regeneration requires complement and myeloid cell activity within the optic nerve. J Neurosci. (2021) 41:8508–31. doi: 10.1523/JNEUROSCI.0555-21.2021, PMID: 34417332 Stasi K Nagel D Yang X Wang RF Ren L Podos SM . Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci. (2006) 47:1024–9. doi: 10.1167/iovs.05-0830, PMID: 16505037 Reinehr S Wulf J Theile J Schulte KK Peters M Fuchshofer R . In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced. Front Immunol. (2024) 15:1296178. doi: 10.3389/fimmu.2024.1296178, PMID: 38515755 Hoppe C Gregory-Ksander M . The role of complement dysregulation in glaucoma. Int J Mol Sci. (2024) 25:2307. doi: 10.3390/ijms25042307, PMID: 38396986 Williams PA Tribble JR Pepper KW Cross SD Morgan BP Morgan JE . Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener. (2016) 11:26. doi: 10.1186/s13024-016-0091-6, PMID: 27048300 Harder JM Braine CE Williams PA Zhu X MacNicoll KH Sousa GL . Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. Proc Natl Acad Sci U.S.A. (2017) 114:E3839–e3848. doi: 10.1073/pnas.1608769114, PMID: 28446616 Chen J Jiang C Huang Q Lin X Wu W Li J . Detection of plasma complement and immune globulin in different sorts of glaucoma. Eur J Ophthalmol. (2022) 32:2907–12. doi: 10.1177/11206721221074202, PMID: 35089079 Meng S Wen D Xiao J Zhang Q Fang W Xue X . Age of rats affects the degree of retinal neuroinflammatory response induced by high acute intraocular pressure. Dis Markers. (2022) 2022:9404977. doi: 10.1155/2022/9404977, PMID: 35132339 Cooke RS Spicer BA Harrison RA Dunstone MA Morgan BP Zelek WM . CD59, disulphide-locked human C9 and horse C9 inhibit human membrane attack complex assembly by similar mechanisms. Immunology. (2025) 176:363–72. doi: 10.1111/imm.70008, PMID: 40523671 Liu Y Zhao W Huang Q Wan L Ren Z Zhang B . Advances in Research on the Release of von Willebrand Factor from Endothelial Cells through the Membrane Attack Complex C5b-9 in Sepsis. J Inflammation Res. (2025) 18:6719–33. doi: 10.2147/JIR.S520726, PMID: 40438181 Becker S Reinehr S Dick HB Joachim SC . Complement activation after induction of ocular hypertension in an animal model. Ophthalmologe. (2015) 112:41–8. doi: 10.1007/s00347-014-3100-6, PMID: 24942221 Lish AM Grogan EFL Benoit CR Pearse RV Heuer SE Luquez T . CLU alleviates Alzheimer's disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density. Neuron. (2025) 113:1925–1946.e11. doi: 10.1016/j.neuron.2025.03.034, PMID: 40311610 Zhang H Jin Q Li J Wang J Li M Yin Q . Astrocyte-derived complement C3 facilitated microglial phagocytosis of synapses in Staphylococcus aureus-associated neurocognitive deficits. PloS Pathog. (2025) 21:e1013126. doi: 10.1371/journal.ppat.1013126, PMID: 40294039 Fang Y Li Y Wang S Deng J Liang J Li S . Corydalis yanhusuo Polysaccharides regulates HPA-axis mediated microglia activation and inhibits astrocyte A1 transformation to improve depression-like behavior. Brain Res. (2025) 1864:149780. doi: 10.1016/j.brainres.2025.149780, PMID: 40513699 Silverman SM Kim BJ Howell GR Miller J John SW Wordinger RJ . C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury. Mol Neurodegener. (2016) 11:24. doi: 10.1186/s13024-016-0089-0, PMID: 27008854 Kuehn MH Kim CY Jiang B Dumitrescu AV Kwon YH . Disruption of the complement cascade delays retinal ganglion cell death following retinal ischemia-reperfusion. Exp Eye Res. (2008) 87:89–95. doi: 10.1016/j.exer.2008.04.012, PMID: 18572163 Bosco A Anderson SR Breen KT Romero CO Steele MR Chiodo VA . Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma. Mol Ther. (2018) 26:2379–96. doi: 10.1016/j.ymthe.2018.08.017, PMID: 30217731 Liu B Neufeld AH . Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy. Neurobiol Dis. (2003) 13:109–23. doi: 10.1016/S0969-9961(03)00010-X, PMID: 12828935 Zhang X Neufeld AH . Activation of the epidermal growth factor receptor in optic nerve astrocytes leads to early and transient induction of cyclooxygenase-2. Invest Ophthalmol Vis Sci. (2005) 46:2035–41. doi: 10.1167/iovs.04-1473, PMID: 15914620 García-Bermúdez MY Freude KK Mouhammad ZA van Wijngaarden P Martin KK Kolko M . Glial cells in glaucoma: friends, foes, and potential therapeutic targets. Front Neurol. (2021) 12:624983. doi: 10.3389/fneur.2021.624983, PMID: 33796062 Shareef S Sawada A Neufeld AH . Isoforms of nitric oxide synthase in the optic nerves of rat eyes with chronic moderately elevated intraocular pressure. Invest Ophthalmol Vis Sci. (1999) 40:2884–91., PMID: 10549648 Husain S Abdul Y Singh S Ahmad A Husain M . Regulation of nitric oxide production by δ-opioid receptors during glaucomatous injury. PloS One. (2014) 9:e110397. doi: 10.1371/journal.pone.0110397, PMID: 25329670 Zhang X Neufeld AH . Signal transduction pathways for epidermal growth factor stimulated cyclooxygenase-2 induction in astrocytes. Exp Eye Res. (2007) 85:280–8. doi: 10.1016/j.exer.2007.05.002, PMID: 17604021 Deng C Chen S Li X Luo H Zhang Q Hu P . Role of the PGE2 receptor in ischemia-reperfusion injury of the rat retina. Mol Vis. (2020) 26:36–47., PMID: 32165825 Lozano DC Choe TE Cepurna WO Morrison JC Johnson EC . Early optic nerve head glial proliferation and jak-stat pathway activation in chronic experimental glaucoma. Invest Ophthalmol Vis Sci. (2019) 60:921–32. doi: 10.1167/iovs.18-25700, PMID: 30835784 Jain M Singh MK Shyam H Mishra A Kumar S Kumar A . Role of JAK/STAT in the neuroinflammation and its association with neurological disorders. Ann Neurosci. (2021) 28:191–200. doi: 10.1177/09727531211070532, PMID: 35341232 Li Q Cheng Y Zhang S Sun X Wu JJJon . TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway. J Neuroinflammation. (2021) 18:271. doi: 10.1186/s12974-021-02315-8, PMID: 34789280 Salkar A Wall RV Basavarajappa D Chitranshi N Parilla GE Mirzaei M . Glial cell activation and immune responses in glaucoma: A systematic review of human postmortem studies of the retina and optic nerve. Aging Dis. (2024) 15:2069–83. doi: 10.14336/AD.2024.0103, PMID: 38502591 Wawrzyniak A Krawczyk-Marć I Żuryń A Walocha J Balawender KJIJoMS . Diversity, functional complexity, and translational potential of glial cells in the central nervous system. Int J Mol Sci. (2025) 26:9080. doi: 10.3390/ijms26189080, PMID: 41009644 Bou Ghanem GO Koktysh D Baratta RO Del Buono BJ Schlumpf E Wareham LK . Collagen mimetic peptides promote repair of MMP-1-damaged collagen in the rodent sclera and optic nerve head. Int J Mol Sci. (2023) 24:17031. doi: 10.3390/ijms242317031, PMID: 38069354 Williams PA Braine CE Kizhatil K Foxworth NE Tolman NG Harder JM . Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma. Mol Neurodegener. (2019) 14:6. doi: 10.1186/s13024-018-0303-3, PMID: 30670050 Margeta MA Lad EM Proia AD . CD163+ macrophages infiltrate axon bundles of postmortem optic nerves with glaucoma. Graefes Arch Clin Exp Ophthalmol. (2018) 256:2449–56. doi: 10.1007/s00417-018-4081-y, PMID: 30073622 Gu X Chen X Zhang X Liu K Li JJ Lv W . Macrophage-induced integrin signaling promotes Schlemm's canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy. Cell Rep. (2024) 43:113799. doi: 10.1016/j.celrep.2024.113799, PMID: 38367239 Cameron EG Nahmou M Toth AB Heo L Tanasa B Dalal R . A molecular switch for neuroprotective astrocyte reactivity. Nature. (2024) 626:574–82. doi: 10.1038/s41586-023-06935-3, PMID: 38086421 Howell GR Soto I Zhu X Ryan M Macalinao DG Sousa GL . Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest. (2012) 122:1246–61. doi: 10.1172/JCI61135, PMID: 22426214 Williams PA Braine CE Foxworth NE Cochran KE John SWM . GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma. J Neuroinflamm. (2017) 14:93. doi: 10.1186/s12974-017-0868-8, PMID: 28446179 Wang L Wei X . T cell-mediated autoimmunity in glaucoma neurodegeneration. J.F.I.I. (2021) 12:803485. doi: 10.3389/fimmu.2021.803485, PMID: 34975917 Tezel G . The role of glia, mitochondria, and the immune system in glaucoma. Invest Ophthalmol Vis Sci. (2009) 50:1001–12. doi: 10.1167/iovs.08-2717, PMID: 19244206 Chen PJ Wang YL Kuo LM Lin CF Chen CY . Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα. Sci Rep. (2016) 6:26554. doi: 10.1038/srep26554, PMID: 27212040 Tanigami H Okamoto T Yasue Y Shimaoka M . Astroglial integrins in the development and regulation of neurovascular units. Pain Res Treat. (2012) 2012:964652. doi: 10.1155/2012/964652, PMID: 23304493 Tehrani S Davis L Cepurna WO Choe TE Lozano DC Monfared A . Astrocyte structural and molecular response to elevated intraocular pressure occurs rapidly and precedes axonal tubulin rearrangement within the optic nerve head in a rat model. PloS One. (2016) 11:e0167364. doi: 10.1371/journal.pone.0167364, PMID: 27893827 Margeta MA Yin Z Madore C Pitts KM Letcher SM Tang J . Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma. Immunity. (2022) 55:1627–1644.e7. doi: 10.1016/j.immuni.2022.07.014, PMID: 35977543 Margeta MA Letcher SM Igo RP Cooke Bailey JN Pasquale LR . Association of APOE with primary open-angle glaucoma suggests a protective effect for APOE ϵ4. Invest Ophthalmol Vis Sci. (2020) 61:3. doi: 10.1167/iovs.61.8.3, PMID: 32614373 Wu X Pan G Chang L Liu Q Liu Y Zhang W . Endoplasmic reticulum stress-induced triggering receptor expressed on myeloid cells 2 (TREM2) downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease. J Am Heart Assoc. (2025) 14:e041220. doi: 10.1161/JAHA.124.041220, PMID: 40551335 Fremuth LE Hu H van de Vlekkert D Annunziata I Weesner JA Alessandra dA . Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation. Cell Rep. (2025) 44:115204. doi: 10.1016/j.celrep.2024.115204, PMID: 39817909 Shi H Yin Z Koronyo Y Fuchs DT Sheyn J Davis MR . Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-induced retinal vasculopathy by limiting Clec7a/Galectin-3(+) neurodegenerative microglia. Acta Neuropathol Commun. (2022) 10:136. doi: 10.1186/s40478-022-01439-z, PMID: 36076283 Méndez-Salcido FA Torres-Flores MI Ordaz B Peña-Ortega F . Abnormal innate and learned behavior induced by neuron-microglia miscommunication is related to CA3 reconfiguration. Glia. (2022) 70:1630–51. doi: 10.1002/glia.24185, PMID: 35535571 Zheng L Wang Y Shao B Zhou H Li X Zhang C . Multiple mild stimulations reduce membrane distribution of CX3CR1 promoted by annexin a1 in microglia to attenuate excessive dendritic spine pruning and cognitive deficits caused by a transient ischemic attack in mice. Neurosci Bull. (2022) 38:753–68. doi: 10.1007/s12264-022-00847-4, PMID: 35352285 Yu C Lad EM Mathew R Littleton S Chen Y Schlepckow K . Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions. bioRxiv. (2023) 221:e20231011. doi: 10.1101/2023.07.19.549403, PMID: 37502831 Won W Bhalla M Lee JH Lee CJ . Astrocytes as key regulators of neural signaling in health and disease. Annu Rev Neurosci. (2025) 48:251–76. doi: 10.1146/annurev-neuro-112723-035356, PMID: 40067961 Yang SS Brooks NAH Da Silva DE Gibon J Islam H Klegeris A . Extracellular ATP regulates phagocytic activity, mitochondrial respiration, and cytokine secretion of human astrocytic cells. Purinergic Signal. (2025) 21:485–98. doi: 10.1007/s11302-025-10066-x, PMID: 39833586 Bijelić DD Milićević KD Lazarević MN Miljković DM Bogdanović Pristov JJ Savić DZ . Central nervous system-infiltrated immune cells induce calcium increase in astrocytes via astroglial purinergic signaling. J Neurosci Res. (2020) 98:2317–32. doi: 10.1002/jnr.24699, PMID: 32799373 Zheng H Liu Q Zhou S Luo H Zhang W . Role and therapeutic targets of P2X7 receptors in neurodegenerative diseases. Front Immunol. (2024) 15:1345625. doi: 10.3389/fimmu.2024.1345625, PMID: 38370420 Lagos-Cabré R Alvarez A Kong M Burgos-Bravo F Cárdenas A Rojas-Mancilla E . α(V)β(3) Integrin regulates astrocyte reactivity. J Neuroinflamm. (2017) 14:194. doi: 10.1186/s12974-017-0968-5, PMID: 28962574 Miao Y Zhao GL Cheng S Wang Z Yang XL . Activation of retinal glial cells contributes to the degeneration of ganglion cells in experimental glaucoma. Prog Retin Eye Res. (2023) 93:101169. doi: 10.1016/j.preteyeres.2023.101169, PMID: 36736070 Shinozaki Y Leung A Namekata K Saitoh S Nguyen HB Takeda A . Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy. Sci Adv. (2022) 8:eabq1081. doi: 10.1126/sciadv.abq1081, PMID: 36332025

Edited by: Danian Chen, Sichuan University, China

Reviewed by: Yu Lin, Shanghai Roche Pharmaceutical Co., Ltd, China

Xiangyu Fu, Sichuan University, China

Jishuang Gu, First Affiliated Hospital of Jilin University, China