Uveitis, a complicated group of ocular inflammatory diseases, can be affected by massive pathogenic contributors such as infection, autoimmunity, and genetics. Although it is well known that many pathological changes, including disorders of the immune system and disruption of the blood-retinal barrier, count much in the onset and progression of uveitis, there is a paucity of safe and effective treatments, which has exceedingly hindered the appropriate treatment of uveitis. As innate immune cells in the retina, microglia occupy a salient position in retinal homeostasis. Many studies have reported the activation of microglia in uveitis and the mitigation of uveitis by interfering with microglial reactivity, which strongly implicates microglia as a therapeutic target. However, it has been increasingly recognized that microglia are a nonhomogeneous population under different physiological and pathological conditions, which makes it essential to thoroughly have knowledge of their specific characteristics. The paper outlines the various properties of activated microglia in uveitis, summarizes the connections between their polarization patterns and the manifestations of uveitis, and ultimately is intended to enhance the understanding of microglial versatility and expedite the exploration of promising strategies for visual protection.

As a group of common blinding ophthalmic diseases with intricate etiologies, uveitis is clinically characterized by the inflammatory/immune reaction of multiple ocular tissues, including the iris, ciliary body, choroid, and even the vitreous body and retina [1]. Although definite pathological processes remain to be further clarified, it is universally acknowledged that an imbalance in the inflammatory/immune response and the destruction of the blood-retinal barrier (BRB) account for much in the pathogenesis of uveitis [2]. Therefore, it is of critical significance to microscopically understand these processes and explore possible protective strategies for improving the visual prognosis of patients with uveitis.

Microglia, which are resident glial cells in the retina, have pleiotropic effects on various physiological and/or pathological conditions, including the trigger and transformation of inflammatory/immune response and the formation and maintenance of the retinal vascular system [3]. Mounting evidence has indicated that activated microglia may serve as a crucial element during the pathogenesis of uveitis. For example, a conspicuous augmentation of microglial density has been recorded around the optic nerve papilla and retinal vessels on the 14th day after the establishment of experimental autoimmune uveitis (EAU) through in vivo multimodal imaging technology [4]. Furthermore, Berasategui et al. [5] have delineated a positive correlation between the number of hyperreflective foci considered microglia and the thickness of the central macula, as well as their negative link with the improvement in visual function among non-infective uveitis subjects with macular edema. Together, it may be meaningful to investigate the role of activated microglia in the development of uveitis. This review aimed to summarize the latest research progress on the role of microglial reactivity in the occurrence and progression of uveitis by sketching related research and providing potential therapeutic strategies for the future treatment of uveitis from a novel perspective.

Under healthy conditions, microglia primarily perform immune surveillance by continuously scanning the surface of their neighbors with random and repeated stretching of their processes [3]. However, the results of our research and that of many other groups have shown that once encountering stimuli, microglia are immediately activated, showing such transmutations as the morphological transition from branching to amoebic, the positional migration from the inner retina to the injured area, the propagation of their population, and the secretion of proinflammatory and anti-inflammatory components [3, 6, 7]. Besides, studies have suggested that microglia anatomically connect with retinal capillaries and neuronal synapses to form a “neurovascular unit” (shown in Fig. 1a), the structure abnormality of which will bring about an array of pathological processes through the imbalance of vascular diameter and blood flow [8]. Systematically, during the early response stage to noxious stimuli, microglia are rapidly recruited, abundantly accumulate around retinal vessels, and then extensively secrete inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and peroxides [9, 10], as well as major histocompatibility complex (MHC) class II molecules [11]. Next, a corrosive effect is induced on the structure of inner BRB by microglia via magnifying the amplitude of inflammatory response, participating in the process of antigen presentation, and promoting the adhesion of peripheral macrophages towards retinal capillaries and their infiltration into retinal tissues [12, 13], whereas the depletion of retinal microglia impedes the generation of cytokines and prevents the dissolution of BRB [14]. Briefly, findings above demonstrate that microglia yield a chief role in the pathology of uveitis, and controlling their reactivity may be a possible intervention target for rescuing the visual function of uveitis patients.

Fig. 1.

Schematic representation of the effect of retinal microglia. a Microglia are involved in the formation of “neurovascular unit.” b Differential response of microglia to various pathogenic stimuli. LPS, lipopolysaccharide; IFN, interferon; IL, interleukin; CD, cluster differentiation; MHC, major histocompatibility complex; ROS, reactive oxygen species; TNF, tumor necrosis factor; iNOS, inducible nitric oxide synthase; Arg, arginine; TGF, transforming growth factor.

Fig. 1.

Schematic representation of the effect of retinal microglia. a Microglia are involved in the formation of “neurovascular unit.” b Differential response of microglia to various pathogenic stimuli. LPS, lipopolysaccharide; IFN, interferon; IL, interleukin; CD, cluster differentiation; MHC, major histocompatibility complex; ROS, reactive oxygen species; TNF, tumor necrosis factor; iNOS, inducible nitric oxide synthase; Arg, arginine; TGF, transforming growth factor.

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Built on some latest techniques like cell lineage tracing and single-cell sequencing, a collection of research studies has revealed retinal microglia as a set of related but discrepant cell colonies. On one hand, from the perspective of their inherent evolutionary codes, researchers have repeatedly proven the intrinsic pleiotropic development of retinal microglia. For instance, while microglia with weak positive immunolabelling for IL-34 are mainly located in the outer plexiform layer, those with strong positive immunoreactivity largely reside in the inner plexiform layer [15]. Anderson et al. [16] also identified 6 diversified microglial subsets in mouse retinas and detected the spontaneous adjustment of their transcriptional profiles in pace with disparate life gradations. Moreover, with the formation of retinal vascularization, microglia gradually shift to retinal areas with stronger matrix stiffness, accompanied by the emergence of cell polarization defined by the dissimilar ramification index [17]. On the other hand, with respect to external stimuli, the polarization of microglia can be influenced by diverse microenvironments. When injury occurs, microglia undergo transcriptional reprogramming, where static and various activated subtypes of microglia are detected simultaneously [15]. Meantime, the expression of genes associated with maintaining homeostasis decreases, while those concerning facilitating neurodegeneration increase [15], and their morphologies also undergo corresponding changes [18].

In order to interpret the phenotypic transformation of microglia more clearly, researchers currently classify reactive microglia into two communities, namely the M1 subgroup being activated via the classical pathway and the M2 subgroup being activated by the alternative mechanism. Collectively, under the stimulation of interferon-γ or lipopolysaccharide, microglia exhibit the M1 phenotype marked by CD16/32, CD40, CD68, CD86, and MHC-Ⅱ, while after being irritated by IL-4 and IL-13, microglia develop the M2 phenotype expressing CD163, CD206, arginase-1 (Arg-1), FIZZ1, and Ym-1 (also known as chitinase 3) [19, 20] (shown in Fig. 1b). Discrepant microglial subtypes possess distinguished metabolic patterns, and the unique intermediates determine their characteristic functions [21‒23]. Specifically, although mitochondrial oxidative phosphorylation efficiently produces enormous ATP, the glycolysis pathway dominates in M1 microglia to acquire energy more quickly, resulting in the more accumulation of lactic acid and the substantial production of intermediates that promote cytokine induction. During this process, the release of inflammatory mediators such as IL-1β and TNF-α is enhanced, and microglial phagocytosis of pathogens is strengthened by metabolites including reactive oxygen species (ROS) and nitric oxide (NO). In contrast, M2 microglia, which are tightly related to some anti-inflammatory molecules involving IL-4, IL-10, IL-13, and transforming growth factor beta (TGF-β) elementally employ the channel of oxidative phosphorylation to get energy. Then, arginine is converted to ornithine, and such biotransformation of substances as polyamine synthesis, fibrosis, and extracellular matrix remodeling ensue to regulate cell proliferation and tissue repair [24] (shown in Fig. 1b). In uveitis, research studies have detected the co-existence of initiators of the classic activation and the alternative activation of microglia in the aqueous humor of clinical patients and in the retina of experimental uveitis animal models [25‒27], which suggests the possibility of microglial M1/M2 differentiation during the pathology of uveitis.

Those differences lead to the individual expression of microglial genes, which challenges people to propose exclusive biomarkers to differentiate microglia subsets. Nowadays, such a finding has aroused mighty attention that heaps of biomarkers used to be adopted in the past, including F4/80, CD11b (alias OX42), ionized calcium binding adapter molecule-1 (also known as allograft inflammatory factor-1), chemokine (C-X3-C motif) receptor 1, colony-stimulating factor-1 receptor, and translocator protein, which can also be presented on the surface of infiltrating macrophages and other cells [28‒30]. Thus, there are many limitations to continue to take them as indicators of microglia. Recently, new markers have been applied in scientific research. As an illustration, transmembrane protein 119 (TMEM119), sialic acid-binding immunoglobulin-like lectin H, and secreted protein acidic and rich in cysteine have been discovered to be relatively enriched in retinal microglia [31]. Besides, the expression of TMEM119 [32] and purinergic receptor P2Y, G protein coupled 12 (P2ry12) [33] have been used to stain microglia in plenty of studies and have succeeded to acquire microglial contour well. But their sensitivity remains to be confirmed. Just like what was observed in the study by Kenkhuis and his team [34], P2ry12 and TMEM119 cannot be detected on all microglia and are preferentially expressed depending on different physiological and/or pathological surroundings, so it is unwise to regard them as stable and sweeping biomarkers of microglia, not to mention the fact that infiltrating macrophages can also express those markers de novo under pathological conditions [35, 36]. Moreover, a large number of studies have verified that the level of TMEM119 protein in microglia varies in the brain and retina depending on location and age, and Müller cells, peripheral follicular dendritic cells, and brown adipose tissue can also exhibit immunoreactivity for TMEM119 [37, 38]. What’s more, as evidenced in the light-injury model, despite the low expression of P2ry12, TMEM119, and sialic acid-binding immunoglobulin-like lectin H, subretinal microglia contain high levels of galectin-3 and CD68 [31]; however, the two factors can be shared by subretinal microglia and the recruited macrophages in Aire−/− mice that spontaneously and progressively developing the manifestations of uveoretinitis [35]. As a result, it seems that these markers are not suitable to identify microglia, and the investigation of more proper biomarkers for microglia population is ongoing. Conclusively, given that microglial phenotypes vary depending on their location and stimuli, it may be feasible to identify microglia by combining many indicators such as disease type, cell localization, and multiple surface markers.

Confined by several restrictions, like the complexity of patients with uveitis and the difficulty of accessing clinical samples, researchers have performed advanced studies using two animal models of uveitis: EAU and endotoxin-induced uveitis (EIU). Studies have certified microglial activation in EAU, where neutrophils and other immune cells invade blood vessels around the retina and choroid and the blood flow of deep capillaries is significantly reduced [39]. Similarly, there is the swift conversion of microglia in EIU, where the inflammatory response peaks at the 18th h and subsides within 2 weeks [40]. Intensive studies have shown that the pharmacological depletion of microglia prevents the decomposition of BRB, suppresses the infiltration of inflammatory cells into the retina, and averts visual impairment in both EAU [13] and EIU [14], indicating a role of microglia in the pathogenesis of uveitis.

For reasons in question, multitude of investigators have been seeking therapeutic measures for uveitis by intervening microglial reactivity, and a variety of medications have been attested to be curative. For example, dexamethasone remarkably bates the density of microglia, the levels of inflammatory cytokines, and the scores of disease symptoms and visibly preserves the retinal structure and function in EAU [41, 42]. Blocking the effect of galectin-3 [43] or nuclear factor erythroid 2-related factor 2 [44] robustly decreases the activation of microglia and inflammatory pathways and the release of proinflammatory factors, ultimately attenuating the clinical and histological manifestations of EAU. Additionally, microglial reactivity and the inflammatory response are substantially impeded by a single subcutaneous injection of minocycline hydrogel loaded on nanocomposite, resulting in a notable decrease in EAU scores [45]. What’s more, research on the EIU model has also drawn similar conclusions. Evidence shows that αB-crystallin [46], tetramethylpyrazine [47], minocycline [48], theissenolactone C [49], and an inhibitor of phosphodiesterase-4 [50] can effectively inactivate microglia and alleviate the ocular inflammation of EIU.

Further in-depth studies concerning the spatiotemporally heterogeneous activation of microglia in the pathogenesis of uveitis provide an opportunity to observe microglia thoroughly. As early as 2001, Fauser et al. [51] emphasized the chronological activation of microglia in the distal optic nerve and optic tract and delineated differences in microglial marker expression. Likewise, lipopolysaccharide boosts the adhesion of microglia to retinal vessels in the early stage of EIU, and microglia with pleiomorphic appearances emerge at 48 h, while those with dendritic figures dominate the entire retina after 72 h and revert to a resting status on the 14th day [12]. In recent years, Bell et al. [40] have depicted the dynamic activation of microglia in various stages of EIU via applying single-cell mRNA-sequencing. For instance, while the iNOS signal pathway was promptly activated at 4 h after EIU and quickly returned to baseline at 18 h, the signal of eukaryotic initiation factor 2 appeared to have no notable change at 4 h but was strikingly activated at 18 h, and restored to normal within 2 weeks.

At the same time, a growing number of discoveries have demonstrated the dual roles of microglia in uveitis, namely the benign or deleterious effects owing to the high diversity of their phenotypes. Accordingly, how to sufficiently exploit the beneficial aspects and avoid the detrimental functions of microglia has become a research hotspot. N6-methyladenosine (m6A) is a posttranscriptional modification that can affect the stability of RNAs. Studies have discovered that m6A-binding protein YTH domain containing 1 (YTHDC1), which was decreased in the retinal microglia of EAU and Aire−/− mice [52], contributes to maintaining the stability of Sirtuin 1 mRNA and hinders the M1 polarization of microglia. Aryl hydrocarbon receptor has been reported to be related to inflammation. Huang and colleagues [53] have authenticated that knockout of this gene was conducive to M1 polarization of microglia/macrophages and impelled the more severe EAU symptoms, while consolidating its effect could safeguard the integrity of BRB and shift microglia/macrophages from M1 to M2. Additionally, icariin favored the switch of retinal microglia from M1 to M2 and relieved EAU by raising the level of peroxiredoxin-3 [54]. Also, minocycline suppressed the activation of microglia, kept down the expression of MHC-Ⅱ, sustained the integrity of BRB, and mitigated the development of EAU, and these effects persisted even if inflammation had been initiated [55]. Although minocycline treatment fails to mitigate EAU by eliminating microglia in the late stage of uveitis [13], this cannot be directly attributed to other effects, such as remodeling the intestinal microenvironment [55]. Further research is needed to characterize changes in microglial subsets during EAU, considering minocycline’s ability to modulate microglial polarization [6, 56]. Besides, among relevant studies of EIU, Cheng et al. [57] displayed a change of retinal microglia from the proinflammatory M1 subtype to the anti-inflammatory M2 subtype by inhibiting Notch1 signaling, where retinal ganglion cell apoptosis was inhibited and retinal function was conserved. In addition, intravitreal injection of anti-VEGF antibodies abates the number of activated microglia/macrophages and iNOS+ microglia in the retina and choroid, although no transparent improvement of EIU symptoms was observed [58].

Finally, it is profound to conduct further research on the activation of microglia in uveitis patients by establishing an extensive and reliable clinical biological sample library and developing and utilizing the latest non-invasive in vivo imaging technologies. A stratified analysis based on factors, such as race, sex, disease type, and disease course, will be necessary to understand the exact role of microglia in the pathogenesis of uveitis.

Uveitis usually acts as a kind of volatile and refractory ophthalmic conditions, which imposes tremendous burdens on sufferers. Studies have exhibited the possible role of retinal microglia in the initiation and progression of uveitis by modifying the inflammatory/immune response and the integrity of the BRB in the retina. Therefore, it may be of considerable significance to target microglial reactivity to cure uveitis. However, the intense heterogeneity of microglia severely cripples the possibility of understanding their functions. Further, the existing overwhelming majority of studies dualistically divide them into the proinflammatory M1 subset and the anti-inflammatory M2 subset, and current generic microglial biomarkers are not yet of adequate specificity and sensitivity, which cannot meet the ever-growing demand for precision medicine. Besides, the fact that invasive monocyte-derived macrophages share the bulk of markers of microglia aggravates the embarrassing plight. Thus, it entails the formation of comprehensively utilizing manifold individualized techniques and analytic methods based on stimuli and spatiotemporal traits to further determine the biological characteristics of individual microglia. Finally, it will be expectable to more accurately utilize the beneficial attributes of microglia and avoid their possible detriments in the future treatments of uveitis.

The authors have no conflicts of interest to declare.

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81970792 and 82171040) and the Medical Science and Technology Project of the Health Commission of Henan Province (Grant No. YXKC2020026).

Liping Du proposed the scheme of the study, conceptualized the framework of the paper, and modified the manuscript. Both Wenna Gao and Xuemin Jin were responsible for the literature search and detail extraction. Wenna Gao also drew up the manuscript. Pengyi Zhou and Haiyan Zhu participated in the discussion and verification of relevant results. Kunpeng Xie and Bo Jin helped to correct mistakes and polish the expression. Every author had look through and agreed with the final version of our manuscript.

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