Microglial cGAS-STING signaling underlies glaucoma pathogenesis.

Characterized by progressive degeneration of retinal ganglion cells (RGCs) and vision loss, glaucoma is the primary cause of irreversible blindness, incurable and affecting over 78 million patients. However, pathogenic mechanisms leading to glaucoma-induced RGC loss are incompletely understood. Unexpectedly, we found that cGAS-STING (2'3'-cyclic GMP-AMP-stimulator of interferon genes) signaling, which surveils displaced double-stranded DNA (dsDNA) in the cytosol and initiates innate immune responses, was robustly activated during glaucoma in retinal microglia in distinct murine models. Global or microglial deletion of STING markedly relieved glaucoma symptoms and protected RGC degeneration and vision loss, while mice bearing genetic cGAS-STING supersensitivity aggravated retinal neuroinflammation and RGC loss. Mechanistically, dsDNA from tissue injury activated microglial cGAS-STING signaling, causing deleterious macroglia reactivity in retinas by cytokine-mediated microglia-macroglia interactions, progressively driving apoptotic death of RGCs. Remarkably, preclinical investigations of targeting cGAS-STING signaling by intraocular injection of TBK1i or anti-IFNAR1 antibody prevented glaucoma-induced losses of RGCs and vision. Therefore, we unravel an essential role of cGAS-STING signaling underlying glaucoma pathogenesis and suggest promising therapeutic strategies for treating this devastating disease.

Irisin attenuates acute glaucoma-induced neuroinflammation by activating microglia-integrin αVß5/AMPK and promoting autophagy.

Neuroinflammation, characterized by microglial activation and the release of multiple inflammatory mediators, is a key factor in acute glaucomatous injury leading to retinal ganglion cell (RGC) death and ultimately irreversible vision loss. Irisin, a novel exercise-induced myokine, has demonstrated anti-inflammatory activity in ischemia/reperfusion injuries across multiple organs and has displayed a significant neuroprotective role in experimental stroke disease models. This study examined the protective impact of irisin and investigated its potential mechanism involved in this process utilizing an acute ocular hypertension (AOH)-induced retinal injury model in mice and a microglia inflammation model induced by lipopolysaccharide (LPS). There was a transient downregulation of irisin in the retina after AOH injury, with parallel emergence of retinal neuroinflammation and RGC death. Irisin attenuated retinal and optic nerve damage and promotes the phenotypic conversion of microglia from M1 to M2. Mechanistically, irisin significantly upregulated the expression of integrin αVß5, p-AMPK, and autophagy-related markers. Integrin αVß5 was highly expressed on microglia but hardly expressed on RGC. The integrin αVß5 inhibitor cilengitide, the AMPK inhibitor dorsomorphin, and the autophagy inhibitor 3-Methyladenine (3-MA) blocked the neuroprotective effects of irisin. Our results suggest irisin attenuates acute glaucoma-induced neuroinflammation and RGC death by activating integrin αVß5/AMPK in microglia and promoting autophagy. It should be considered a potential neuroprotective therapy for acute glaucoma.

Role of T cell-induced autoimmune response in the pathogenesis of glaucoma.

PURPOSE: This review aims to elucidate the role of T cell-induced autoimmune responses in the pathogenesis of glaucoma, focusing on the immunological changes contributing to retinal ganglion cell (RGC) damage. METHODS: A comprehensive review of recent studies examining immunological mechanisms in glaucoma was conducted. This included analyses of T cell interactions, heat shock proteins (HSPs), and resultant autoimmune responses. Key findings from experimental models and clinical observations were synthesized to present a coherent understanding of immune dynamics in glaucoma. RESULTS: Glaucoma is a neurodegenerative disease marked by optic nerve atrophy and irreversible vision loss due to RGC damage. The disease is etiologically heterogeneous, with multiple risk factors and pathogenic mechanisms. Recent research highlights the dual immunomodulatory role of T cells in immune protection and injury. T cells, pre-sensitized by bacterial HSPs, can cross-react with endogenous HSPs in RGCs under stress, leading to autoimmune damage. Elevated levels of HSP autoantibodies and abnormal T cell activity have been observed in glaucoma patients, indicating a significant autoimmune component in disease progression. CONCLUSIONS: T cell-induced autoimmune responses are crucial in the pathogenesis of glaucoma, contributing to RGC degeneration beyond the effects of elevated intraocular pressure. Understanding these immunological mechanisms is vital for developing targeted neuroprotective therapies for glaucoma.

Glial Cell Activation and Immune Responses in Glaucoma: A Systematic Review of Human Postmortem Studies of the Retina and Optic Nerve.

Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised. This review provides a comprehensive summary of neuroinflammatory responses in glaucoma. A systematic search of Medline and Embase for articles published up to 8th March 2023 yielded 32 studies using post-mortem tissues from glaucoma patients. The raw data were extracted from tables and text to calculate the standardized mean differences (SMDs). These studies utilized post-mortem tissues from glaucoma patients, totalling 490 samples, compared with 380 control samples. Among the included studies, 27 reported glial cell activation based on changes to cellular morphology and molecular staining. Molecular changes were predominantly attributed to astrocytes (62.5%) and microglia (15.6%), with some involvement of Muller cells. These glial cell changes included amoeboid microglial cells with increased CD45 or HLA-DR intensity and hypertrophied astrocytes with increased glial fibrillary acidic protein labelling. Further, changes to extracellular matrix proteins like collagen, galectin, and tenascin-C suggested glial cells' influence on structural changes in the optic nerve head. The activation of DAMPs-driven immune response and the classical complement cascade was reported and found to be associated with activated glial cells in glaucomatous tissue. Increased pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also linked to glial cells. Glial cell activation was also associated with mitochondrial, vascular, metabolic and antioxidant component disruptions. Association of the activated glial cells with pro-inflammatory responses, dysregulation of homeostatic components and antigen presentation indicates that glial cell responses influence glaucoma progression. However, the exact mechanism triggering these responses and underlying interactions remains unexplored. This necessitates further research using human samples for an increased understanding of the precise role of neuroinflammation in glaucoma progression.

Immune Responses in the Glaucomatous Retina: Regulation and Dynamics.

Glaucoma is a multifactorial disease resulting in progressive vision loss due to retinal ganglion cell (RGC) dysfunction and death. Early events in the pathobiology of the disease include oxidative, metabolic, or mechanical stress that acts upon RGC, causing these to rapidly release danger signals, including extracellular ATP, resulting in micro- and macroglial activation and neuroinflammation. Danger signaling also leads to the formation of inflammasomes in the retina that enable maturation of proinflammatory cytokines such IL-1ß and IL-18. Chronic neuroinflammation can have directly damaging effects on RGC, but it also creates a proinflammatory environment and compromises the immune privilege of the retina. In particular, continuous synthesis of proinflammatory mediators such as TNFα, IL-1ß, and anaphylatoxins weakens the blood-retina barrier and recruits or activates T-cells. Recent data have demonstrated that adaptive immune responses strongly exacerbate RGC loss in animal models of the disease as T-cells appear to target heat shock proteins displayed on the surface of stressed RGC to cause their apoptotic death. It is possible that dysregulation of these immune responses contributes to the continued loss of RGC in some patients.

Adenosine: The common target between cancer immunotherapy and glaucoma in the eye.

Adenosine, an endogenous purine nucleoside, is a well-known actor of the immune system and the inflammatory response both in physiologic and pathologic conditions. By acting upon particular, G-protein coupled adenosine receptors, i.e., A1, A2- a & b, and A3 receptors mediate a variety of intracellular and immunomodulatory actions. Several studies have elucidated Adenosine's effect and its up-and downstream molecules and enzymes on the anti-tumor response against several types of cancers. We have also targeted a couple of molecules to manipulate this pathway and get the immune system's desired response in our previous experiences. Besides, the outgrowth of the studies on ocular Adenosine in recent years has significantly enhanced the knowledge about Adenosine and its role in ocular immunology and the inflammatory response of the eye. Glaucoma is the second leading cause of blindness globally, and the recent application of Adenosine and its derivatives has shown the critical role of the adenosine pathway in its pathophysiology. However, despite a very promising background, the phase III clinical trial of Trabodenoson failed to achieve the non-inferiority goals of the study. In this review, we discuss different aspects of the abovementioned pathway in ophthalmology and ocular immunology; following a brief evaluation of the current immunotherapeutic strategies, we try to elucidate the links between cancer immunotherapy and glaucoma in order to introduce novel therapeutic targets for glaucoma.

T Cell-Mediated Autoimmunity in Glaucoma Neurodegeneration.

Glaucoma as the leading neurodegenerative disease leads to blindness in 3.6 million people aged 50 years and older worldwide. For many decades, glaucoma therapy has primarily focused on controlling intraocular pressure (IOP) and sound evidence supports its role in delaying the progress of retinal ganglial cell (RGC) damage and protecting patients from vision loss. Meanwhile, accumulating data point to the immune-mediated attack of the neural retina as the underlying pathological process behind glaucoma that may come independent of raised IOP. Recently, some scholars have suggested autoimmune aspects in glaucoma, with autoreactive T cells mediating the chief pathogenic process. This autoimmune process, as well as the pathological features of glaucoma, largely overlaps with other neurodegenerative diseases in the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In addition, immune modulation therapy, which is regarded as a potential solution for glaucoma, has been boosted in trials in some CNS neurodegenerative diseases. Thus, novel insights into the T cell-mediated immunity and treatment in CNS neurodegenerative diseases may serve as valuable inspirations for ophthalmologists. This review focuses on the role of T cell-mediated immunity in the pathogenesis of glaucoma and discusses potential applications of relevant findings of CNS neurodegenerative diseases in future glaucoma research.

T and B Lymphocyte Deficiency in Rag1-/- Mice Reduces Retinal Ganglion Cell Loss in Experimental Glaucoma.

Purpose: We previously demonstrated that passive transfer of lymphocytes from glaucomatous mice induces retinal ganglion cell (RGC) damage in recipient animals, suggesting a role for immune responses in the multifactorial pathophysiology of glaucoma. Here we evaluate whether absence of an adaptive immune response reduces RGC loss in glaucoma. Methods: Elevated intraocular pressure (IOP) was induced in one eye of C57BL/6J (B6) or T- and B-cell-deficient Rag1-/- knockout mice. After 16 weeks RGC density was determined in both the induced and the normotensive contralateral eyes. Data were compared to mice having received injections of "empty" vector (controls). The number of extravascular CD3+ cells in the retinas was determined using FACS. Results: Retinas of eyes with elevated IOP contain significantly more extravasated CD3+ cells than control retinas (46.0 vs. 27.1, P = 0.025). After 16 weeks of elevated IOP the average RGC density in B6 mice decreased by 20.7% (P = 1.9 × 10-4). In contrast, RGC loss in Rag1-/- eyes with elevated IOP was significantly lower (10.3%, P = 0.006 vs. B6). RGC loss was also observed in the contralateral eyes of B6 mice, despite the absence of elevated IOP in those eyes (10.1%; P = 0.008). In RAG1-/- loss in the contralateral eyes was minimal (3.1%) and significantly below that detected in B6 (P = 0.02). Conclusions: Our findings demonstrate that T Rag1-/- mice are significantly protected from glaucomatous RGC loss. In this model, lymphocyte activity contributes to approximately half of all RGC loss in eyes with elevated IOP and to essentially all loss observed in normotensive contralateral eyes.

Increased Hydrostatic Pressure Promotes Primary M1 Reaction and Secondary M2 Polarization in Macrophages.

Patients with chronic anterior uveitis are at particularly high risk of developing secondary glaucoma when corticosteroids [e.g., dexamethasone (Dex)] are used or when inflammatory activity has regressed. Macrophage migration into the eye increases when secondary glaucoma develops and may play an important role in the development of secondary glaucoma. Our aim was to evaluate in vitro if increased hydrostatic pressure and corticosteroids could induce changes in macrophages phenotype. By using a pressure chamber cell culture system, we assessed the effect of increased hydrostatic pressure (HP), inflammation, and immunosuppression (Dex) on the M1/M2 phenotype of macrophages. Bone marrow-derived macrophages (BMDMs) were stimulated with medium, lipopolysaccharide (LPS, 100 ng/ml), Dex (200 ng/ml), or LPS + Dex and incubated with different HP (0, 20, or 60 mmHg) for 2 or 7 days. The numbers of CD86+/CD206- (M1 phenotype), CD86-/CD206+ (M2 phenotype), CD86+/CD206+ (intermediate phenotype), F4/80+/TNF-α+, and F4/80+/IL-10+ macrophages were determined by flow cytometry. TNF-α and IL-10 levels in cell culture supernatants were quantified by ELISA. TNF-α, IL-10, fibronectin, and collagen IV expression in BMDMs were detected by immunofluorescence microscopy. Higher HP polarizes macrophages primarily to an M1 phenotype (LPS, 60 vs. 0 mmHg, d2: p = 0.0034) with less extra cellular matrix (ECM) production and secondary to an M2 phenotype (medium, 60 vs. 0 mmHg, d7: p = 0.0089) (medium, 60 vs. 20 mmHg, d7: p = 0.0433) with enhanced ECM production. Dex induces an M2 phenotype (Dex, medium vs. Dex, d2: p < 0.0001; d7: p < 0.0001) with more ECM production. Higher HP further increased M2 polarization of Dex-treated macrophages (Dex, 60 vs. 0 mmHg, d2: p = 0.0417; d7: p = 0.0454). These changes in the M1/M2 phenotype by high HP or Dex treatment may play a role in the pathogenesis of secondary uveitic glaucoma- or glucocorticoid (GC)-induced glaucoma.

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.

Previous studies demonstrated that retinal damage correlates with a massive remodeling of extracellular matrix (ECM) molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. Ten weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells, and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function were comparable in all groups. Although RGC loss was less severe in KO ONA, WT as well as KO mice displayed a significant cell loss after immunization. Compared to KO ONA, less ßIII-tubulin+ axons, and downregulated oligodendrocyte markers were noted in WT ONA optic nerves. In retina and optic nerve, we found an enhanced GFAP+ staining area of astrocytes in immunized WT. A significantly higher number of retinal Iba1+ microglia was found in WT ONA, while a lower number of Iba1+ cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2, and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb1 expression was measured in KO ONA animals. We conclude that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model for the first time offers the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling.

Molecular changes in glaucomatous trabecular meshwork. Correlations with retinal ganglion cell death and novel strategies for neuroprotection.

Glaucoma is a chronic neurodegenerative disease characterized by retinal ganglion cell loss. Although significant advances in ophthalmologic knowledge and practice have been made, some glaucoma mechanisms are not yet understood, therefore, up to now there is no effective treatment able to ensure healing. Indeed, either pharmacological or surgical approaches to this disease aim in lowering intraocular pressure, which is considered the only modifiable risk factor. However, it is well known that several factors and metabolites are equally (if not more) involved in glaucoma. Oxidative stress, for instance, plays a pivotal role in both glaucoma onset and progression because it is responsible for the trabecular meshwork cell damage and, consequently, for intraocular pressure increase as well as for glaucomatous damage cascade. This review at first shows accurately the molecular-derived dysfunctions in antioxidant system and in mitochondria homeostasis which due to both oxidative stress and aging, lead to a chronic inflammation state, the trabecular meshwork damage as well as the glaucoma neurodegeneration. Therefore, the main molecular events triggered by oxidative stress up to the proapoptotic signals that promote the ganglion cell death have been highlighted. The second part of this review, instead, describes some of neuroprotective agents such as polyphenols or polyunsaturated fatty acids as possible therapeutic source against the propagation of glaucomatous damage.

Microglial changes in the early aging stage in a healthy retina and an experimental glaucoma model.

Glaucoma is an age-related neurodegenerative disease that begins at the onset of aging. In this disease, there is an involvement of the immune system and therefore of the microglia. The purpose of this study is to evaluate the microglial activation using a mouse model of ocular hypertension (OHT) at the onset of aging. For this purpose, we used both naive and ocular hypertensives of 15-month-old mice (early stage of aging). In the latter, we analyzed the OHT eyes and the eyes contralateral to them to compare them with their aged controls. In the eyes of aged naive, aged OHT and aged contralateral eyes, microglial changes were observed compared to the young mice, including: (i) aged naive vs young naive: An increased soma size and vertical processes; (ii) aged OHT eyes vs young OHT eyes: A decrease in the area of the retina occupied by Iba-1 cells and in vertical processes; and (iii) aged contralateral vs young contralateral: A decrease in the soma size and arbor area and an increase in the number of microglia in the outer segment layer. Aged OHT eyes and the eyes contralateral to them showed an up-regulation of the CD68 expression in the branched microglia and a down-regulation in the MHCII and P2RY12 expression with respect to the eyes of young OHT mice. Conclusion: in the early phase of aging, morphological microglial changes along with changes in the expression of MHCII, CD68 and P2RY12, in both naive and OHT mice. These changes appear in aged OHT eyes and the eyes contralateral to them eyes.

A broad perspective on the molecular regulation of retinal ganglion cell degeneration in glaucoma.

Glaucoma is a complex neurodegenerative disease involving RGC axons, somas, and synapses at dendrites and axon terminals. Recent research advancements in the field have revealed a bigger picture of glaucomatous neurodegeneration that encompasses multiple stressors, multiple injury sites, multiple cell types, and multiple signaling pathways for asynchronous degeneration of RGCs during a chronic disease period. Optic nerve head is commonly viewed as the critical site of injury in glaucoma, where early injurious insults initiate distal and proximal signaling for axonal and somatic degeneration. Despite compartmentalized processes for degeneration of RGC axons and somas, there are intricate interactions between the two compartments and mechanistic overlaps between the molecular pathways that mediate degeneration in axonal and somatic compartments. This review summarizes the recent progress in the molecular understanding of RGC degeneration in glaucoma and highlights various etiological paths with biomechanical, metabolic, oxidative, and inflammatory components. Through this growing body of knowledge, the glaucoma community moves closer toward causative treatment of this blinding disease.

The role of commensal microflora-induced T cell responses in glaucoma neurodegeneration.

Over the last decade, new evidence has become increasingly more compelling that commensal microflora profoundly influences the maturation and function of resident immune cells in host physiology. The concept of gut-retina axis is actively being explored. Studies have revealed a critical role of commensal microbes linked with neuronal stress, immune responses, and neurodegeneration in the retina. Microbial dysbiosis changes the blood-retina barrier permeability and modulates T cell-mediated autoimmunity to contribute to the pathogenesis of retinal diseases, such as glaucoma. Heat shock proteins (HSPs), which are evolutionarily conserved, are thought to function both as neuroprotectant and pathogenic antigens of T cells contributing to cell protection and tissue damage, respectively. Activated microglia recruit and interact with T cells during this process. Glaucoma, characterized by the progressive loss of retinal ganglion cells, is the leading cause of irreversible blindness. With nearly 70 million people suffering glaucoma worldwide, which doubles the number of patients with Alzheimer's disease, it represents the most frequent neurodegenerative disease of the central nervous system (CNS). Thus, understanding the mechanism of neurodegeneration in glaucoma and its association with the function of commensal microflora may help unveil the secrets of many neurodegenerative disorders in the CNS and develop novel therapeutic interventions.

The role of neuroinflammation in the pathogenesis of glaucoma neurodegeneration.

The chapter is a review enclosed in the volume "Glaucoma: A pancitopatia of the retina and beyond." No cure exists for glaucoma. Knowledge on the molecular and cellular alterations underlying glaucoma neurodegeneration (GL-ND) includes innovative and path-breaking research on neuroinflammation and neuroprotection. A series of events involving immune response (IR), oxidative stress and gene expression are occurring during the glaucoma course. Uveitic glaucoma (UG) is a prevalent acute/chronic complication, in the setting of chronic anterior chamber inflammation. Managing the disease requires a team approach to guarantee better results for eyes and vision. Advances in biomedicine/biotechnology are driving a tremendous revolution in ophthalmology and ophthalmic research. New diagnostic and imaging modalities, constantly refined, enable outstanding criteria for delimiting glaucomatous neurodegeneration. Moreover, biotherapies that may modulate or inhibit the IR must be considered among the first-line for glaucoma neuroprotection. This review offers the readers useful and practical information on the latest updates in this regard.

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models.

Glaucoma is identified by an irreversible retinal ganglion cell (RGC) loss and optic nerve damage. Over the past few years, the immune system gained importance in its genesis. In a glaucoma-like animal model with intraocular S100B injection, RGC death occurs at 14 days. In an experimental autoimmune glaucoma model with systemic S100B immunization, a loss of RGCs is accompanied by a decreased synaptic signal at 28 days. Here, we aimed to study synaptic alterations in these two models. In one group, rats received a systemic S100B immunization (n = 7/group), while in the other group, S100B was injected intraocularly (n = 6-7/group). Both groups were compared to appropriate controls and investigated after 14 days. While inhibitory post-synapses remained unchanged in both models, excitatory post-synapses degenerated in animals with intraocular S100B injection (p = 0.03). Excitatory pre-synapses tendentially increased in animals with systemic S100B immunization (p = 0.08) and significantly decreased in intraocular ones (p = 0.04). Significantly more n-methyl-d-aspartate (NMDA) receptors (both p ≤ 0.04) as well as gamma-aminobutyric acid (GABA) receptors (both p < 0.03) were observed in S100B animals in both models. We assume that an upregulation of these receptors causes the interacting synapse types to degenerate. Heightened levels of excitatory pre-synapses could be explained by remodeling followed by degeneration.

Glaucoma is an autoimmune disease.

Glaucoma is characterized by retinal ganglion cell (RGC) neurodegeneration. Elevated intraocular pressure (IOP) is a major risk factor however, mechanisms independent of IOP play a role in RGC pathology. Both antibodies and CD4 T-cells as well as microbiota take part in the pathogenesis of both glaucoma and rheumatoid arteritis (RA).Heat shock proteins (HSPs) which originate in bacteria cross-react with RCG epitopes and were involved in rat model of retinal injury. Enhanced expression of HSPs in the retina was associated with glaucoma-like neuropathology and previous studies have also suggested a pathogenic role for HSPs in RA. In view of these data we suggest that glaucoma should be included in the spectrum of autoimmune diseases and that proven medications for RA should be adopted as an innovative IOP -independent therapeutic strategy for glaucoma.

The role of TLR4/NF-κB signaling pathway in activated microglia of rats with chronic high intraocular pressure and vitro scratch injury-induced microglia.

Glaucoma is a kind of blind-causing disease with structural damages of optic nerve and defection of visual field. It is believed that the death of retinal ganglion cell (RGC) is a consequential event of over-reactive immune orchestral cells such as microglia. Previous evidences in animal and clinical studies show the innate immunity plays a pivotal role in neuro-inflammation of glaucoma. Toll-like receptor 4 (TLR4) is expressed on microglia and mediates many neuroinflammatory diseases. We aimed to explore the impacts of high intraocular pressure (IOP) on rat microglia in retina and the regulation of TLR4/NF-κB signaling pathway in scratched microglia cells. In our study, we successfully established chronic high IOP rat model by episcleral vein cauterization (EVC) which behaved like the chronic glaucoma. Besides, we set up an in vitro scratch-induced injury model in rat microglia cells. We found the level of activated microglia cells were significantly increased in the retina of chronic high IOP groups. Moreover, the inhibition of TLR4/NF-κB signaling pathway suppressed the expression of TLR4 protein and mRNA levels of P50, IL-6 and TNF-α. Our original study provided a theoretical basis on targeting TLR4/NF-κB to suppress pro-inflammatory factors releasing in activated microglia and it might be a good treatment target to prevent glaucoma from progressing.

Characteristic Cytokine Profiles of Aqueous Humor in Glaucoma Secondary to Sturge-Weber Syndrome.

Patients with Sturge-Weber syndrome (SWS) are susceptible to ocular complications, and among them, glaucoma is one of the most frequent forms. In current study, we utilized multiplex human cytokine antibody array to simultaneously measure the concentration of 40 cytokines in aqueous humor (AH) of patients with SWS-induced glaucoma (SG), or from patients with senile cataract as controls. Compared with the control group, levels of interleukin (IL)-12p40, macrophage inflammatory protein (MIP)-1d, tumor necrosis factor-alpha (TNF-a), IL-5, IL-7, interleukin-6 receptor (IL-6R), and B lymphocyte chemoattractant (BLC) in AH were significantly higher in SG group. Samples from SG patients displayed significantly lower levels of MIP-1b, IL-6, MIP-1a, and monocyte chemoattractant protein (MCP)-1 than controls. Further analysis showed that IL-7, MIP-1a, TNF-a were positively correlated with intraocular pressure (IOP) in patients with early-onset SG. Moreover, IL-12p40 was negatively correlated with age in patients with SG. These cytokines may make contributions to the immunopathogenesis or progression of glaucoma in patients with SWS.