Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system

Abstract

Retinitis pigmentosa (RP) is an important cause of irreversible blindness worldwide and lacks effective treatment strategies. Although mutations are the primary cause of RP, research over the past decades has shown that neuroinflammation is an important cause of RP progression. Due to the abnormal activation of immunity, continuous sterile inflammation results in neuron loss and structural destruction. Therapies targeting inflammation have shown their potential to attenuate photoreceptor degeneration in preclinical models. Regardless of variations in genetic background, inflammatory modulation is emerging as an important role in the treatment of RP. We summarize the evidence for the role of inflammation in RP and mention therapeutic strategies where available, focusing on the modulation of innate immune signals, including TNFα signaling, TLR signaling, NLRP3 inflammasome activation, chemokine signaling and JAK/STAT signaling. In addition, we describe epigenetic regulation, the gut microbiome and herbal agents as prospective treatment strategies for RP in recent advances.

1 Introduction

1.1 Retinal inflammation and RP

Retinitis pigmentosa (RP) is a category of inherited retinal dystrophies marked by vision loss and, ultimately, blindness. More than 3000 mutations in over 80 distinct genes or loci have been identified as causes of non-syndromic RP (1, 2). These mutations can be transmitted in an autosomal-dominant, autosomal-recessive, or X-linked manner. There are also syndromic forms of RP, such as Usher syndrome and Bardet-Biedl syndrome (3). The prevalence of RP is reported to be 1/3,000 to 1/5,000 (https://www.orpha.net/consor/cgi-bin/index.php?lng=EN). Early in the progression of RP, patients experience night blindness and difficulty with dark adaptation. They gradually lose peripheral vision and develop tunnel vision as the disease advances, indicating the loss of rod function. Cone involvement contributes to visual acuity decline over time, and finally, typically in middle age, central vision loss occurs (2). Due to its clinical and genetic heterogeneity, RP has limited therapeutic options. It has long been recognized that inflammation and immune responses are associated with RP, and this theme has recently gained increasing attention (4–6). Greater understanding of the molecular processes driving RP inflammation is expected to provide new therapeutic approaches independent of the genetic background.

Inflammation activation is a prominent feature of RP. In RP, inflammation is characterized by activation of the innate immune system, including dysfunction of the immune barrier, activation and infiltration of immune cells, and upregulation of topical and peripheral inflammatory factors. Bone-spicule pigmentation, attenuated retinal vessels and waxy pallor of the optic disc are typical clinical manifestations of RP. In addition, inflammatory cells are commonly observed in the vitreous due to the collapse of the blood−retina barrier (BRB). Higher cell density correlates with younger age and impaired visual function (6). In addition, it has been reported that increased aqueous flare in RP patients correlates closely with visual function and the extent of global retinal degeneration (7–11). Aqueous flare is generally seen in individuals with inflammatory ocular disorders, indicating deficits of the blood–aqueous barrier and inflammatory protein/cell leakage (12, 13). BRB disruption begins early in the disease. Prior to the infiltration of inflammatory cells and photoreceptor (PR) starvation, the tight junctions of the retinal pigment epithelium (RPE) and the retinal vasculature become leaky, thereby promoting the formation of an inflammatory milieu and the degeneration of PRs (14–17).

Microglia are essential components of the retinal innate immune system and play a pivotal role in retinal inflammatory responses. Gupta et al. reported that microglial activation is engaged in human RP. With thinning of the PR layer, microglia were observed to infiltrate degenerative foci; these microglia were enlarged amoeboid cells containing rhodopsin-positive cytoplasmic inclusions (18). Microglia promote retinal inflammation via infiltration, phagocytosis, and secretion of proinflammatory mediators, whereas genetic ablation or inhibition of microglial phagocytosis ameliorates PR degeneration in RP model mice (19).

Several studies (6, 20–22) have reported elevated levels of inflammatory factors in serum, vitreous, and aqueous humor, indicating a proactive inflammatory response in RP patients. Immunologic disorders observed in patients with RP are summarized in a previous work (23).

Animal models are essential for the study of RP (24, 25). Activation of the immune system has been detected in various rodent RP animal models (26–28). Due to this similarity, animal models are indispensable for clarifying the pathogenesis of RP and developing treatments. Clinically, synthetic corticosteroids with potent anti-inflammatory and immunosuppressive properties are used in treatments for RP-related cystoid macular edema (29). In RP models, it also works. In RCS and rhodopsin mutant model S334ter-4 rats, fluocinolone acetonide treatment markedly protects PR from degeneration and suppresses microglial activity (30, 31). In combination with polyamidoamine dendrimers, fluocinolone acetonide selectively targets the microglia localized in the outer retina where degeneration is ongoing (32). Dexamethasone administration to rd10 mice reduces retinal inflammation, restores cone structure and function, and preserves RPE integrity by preserving ZO-1 density (15, 33).

1.2 Microglia and Müller glia in RP retinas

Microglial activation is a sign of neuroinflammation. Retinal resident microglia arise from yolk sac erythromyeloid progenitors, comprising 85% of total retina macrophages (34–36). They colonize the developing retina during embryogenesis, shape the retina by secreting neurotrophic factors, engulf and eliminate unwanted neurons and synapses, and engage in vascular development of the eye (37–39). In postnatal retinas, microglia are maintained throughout life independent of circulating monocytes and by self-renewal (34, 40, 41).

Microglia express a variety of receptors (e.g., CX3CR1, TLRs, IL-1R, and TNFR) that allow them to detect environmental changes and initiate the inflammatory signal cascade (42). Microglia activation induces a robust inflammatory response, including the release of proinflammatory factors, phagocytosis, and inflammatory cell recruitment. Excessive microglial phagocytosis contributes to local inflammation and neurodegeneration (43, 44).

Classically, activated microglia were categorized into two groups: M1 (classically activated) and M2 (alternatively activated), with the belief that M1 microglia secrete proinflammatory factors such as TNFα, IL-1β, IL-6, and inducible nitric oxide synthase (iNOS) that fuel inflammation, whereas M2 microglia produce anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13, IL-18) that are beneficial for damage repair (45). Recent research, however, suggests that the microglial phenotype varies in response to environmental changes (46).

In healthy retinas, microglia tile the inner and outer plexiform layers without overlapping (37), where they are ramified cells responsible for immune surveillance and maintenance of synaptic structure and transmission (47–50). In response to insults, microglia rapidly change into an amoeboid appearance and migrate into lesion areas, removing dead/dying neurons and neuronal debris while concurrently releasing proinflammatory factors as well as protective cytokines and trophic factors to repair damage and restore homeostasis (51), after which microglia recover to the “resting” state; this process usually results in minimal retinal remodeling.

In RP retinas, initial mutation-driven PR degeneration increases extracellular signal molecules (e.g., ATP, HSPs, HMGB1, DNA, and many others) termed damage-associated molecular patterns (DAMPs) (52–56). The “eat-me” signal, phosphatidylserine, appears on stressed rods (19). Microglia proliferate and infiltrate the PR layer and subretinal space, where they function as reactive phagocytes, phagocytose dead and stressed PRs, secrete proinflammatory cytokines (e.g., TNFα and IL-1β) and chemokines (e.g., CCL2 and RANTES), and recruit infiltrating immune cells (19, 24, 57, 58). Due to this mutant genetic background, however, microglial activation persists, and the continuous production of inflammatory and cytotoxic factors exacerbates PR loss until the late stage, at which point PRs mostly die and the retinal structure is severely damaged (59).

Müller glia are another group of retinal cells engaged in degeneration. Müller glia are retinal macroglia that provide homeostasis, metabolism, and functional support for neurons (60). Depending on the severity, the Müller glial response to injury refers to reactive gliosis accompanied by Müller proliferation or not. Reactive gliosis can be beneficial because it releases protective factors such as neurotrophic factors, whereas prolonged gliosis is detrimental and generally results in neurodegeneration (61). Müller glia are potential modulators of retinal inflammation. Upon BRB disruption, Müller glia compensate for RPE deficiency by sealing the leaky choroid and inducing claudin-5 expression (14). Müller glia share characteristics with immune cells. Müller glia express multiple cytokine receptors and are a major source of cytokines and inflammatory factors (62). Proteomic evidence supports the capacity of Müller glia for antigen presentation and inflammatory signaling transduction in response to immune stimulation (63, 64). Müller glia contribute to the phagocytic clearance of dead PRs (65). Moreover, the interaction between Müller glia and microglia modulates retinal inflammation and degeneration (66–68).

As the predominant glial population of the retina, Müller glia are abundant and widely distributed. Müller glia traverse the thickness of the neuroretina structurally, allowing them to keep touch with all types of retinal cells. Due to its neurotrophic function and regeneration potential, the Müller cell has been studied in a variety of degenerative retinal disorders (69). In actuality, Müller glia are also intimately linked to retinal inflammation. For more information about how Müller glia interact with the innate immune system and monitor retinal inflammation, we refer the reader to this article (70).

Complicated mechanisms are involved in the regulation of retinal inflammation in RP. Microglia and Müller glia are major cellular populations that express and modulate these signaling pathways (Figure 1). Here, we review treatment strategies from the perspective of inflammation management (Table 1), focus on molecular mechanisms related to immunomodulation, and discuss new findings regarding epigenetic modification and the gut microbiome as novel therapies for RP.

Figure 1

2 Mechanisms related to inflammation in RP

2.1 TNFα signaling

Tumor necrosis factor α (TNFα) is a strong proinflammatory cytokine that plays vital roles in immune modulation, cell proliferation, differentiation, and apoptosis. TNFα is produced predominantly by T and innate immune cells and is initially synthesized as transmembrane protein (tmTNFα), a precursor that requires proteolytic cleavage by TNFα-converting enzyme (also ADAM17) to release a soluble form (sTNFα) (124). Both tmTNFα and sTNFα are implicated in the inflammatory response.

TNFα initiates a signal cascade by binding to its receptors, TNFR1 and TNFR2. TNFR1 is activated by both tmTNFα and sTNFα, whereas TNFR2 is proposed to be fully activated primarily by tmTNFα (125). Ligand binding to TNFR1 recruits the adaptor molecule TNFR1-associated death domain protein, which then leads to the assembly of several signaling complexes known as complexes I, IIa, IIb, and IIc. Complex I formation stimulates nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). Complex IIa and IIb assembly activates caspase-8 and facilitates apoptosis, and complex IIc formation activates the mixed lineage kinase domain-like protein and induces necroptosis and inflammation. TNFR2 stimulation activates NF-κB, MAPKs, and protein kinase B (125).

TNFα is postulated to participate in the pathogenesis of RP (74). TNFα and TNFR expression levels are elevated in the retina of RP models and in the aqueous humor of RP patients (24, 74, 126–128); microglia (129) and Müller glia (130, 131) are the primary cellular sources of TNFα. TNFα signaling has been found to mediate PR death via RIP1/3-related necrosis and caspase3/7-dependent apoptosis, in addition to triggering proinflammatory signaling in the RP retina (73, 126).

2.1.1 NGF receptor and TNFα production

Increased TNFα expression in the retina is linked to nerve growth factor (NGF) receptor activation. Müller glia in rhodopsin mutant RP model RHOP347S mice upregulate the expression of TrkC. T1, a truncated TrkC receptor isoform, and its ligand NT-3. TrkC.T1 increases local TNFα production by activating MAPK/Erk, ultimately leading to PR death. This process can be reversed by genetic knockdown of TrkC.T1, TrkC antagonism, or MAPK/Erk inhibition (71). Similarly, TrkC.T1 knockout (KO) and TrkC inhibition increased retinal ganglion cell survival in a mouse model of glaucoma by reducing TNFα production (132), implying that TrkC.T1 is upstream of TNFα.

It has been reported that microglia-derived proNGF facilitates PR death via p75NTR (133), proNGF binding to p75NTR in Müller glia induces robust expression of TNFα and TNFα-dependent neuron death in rodent retina (131, 134), the expression levels of proNGF and p75NTR are increased in the retina of rd10 at early degenerative stages, pharmacological antagonism of p75NTR with THX-B ((1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6tetrahydro-purin-7-yl)-acetyl]-urea)) affords neuroprotection to PRs, and the treatment also mediates reduction of TNFα production, microglial activation, and reactive gliosis (72).

2.1.2 TNFα inhibition

TNFα knockdown in the T17M rhodopsin mutant mouse model reduces PR death and PR-related functional loss, and this neuroprotective effect is associated with reductions in proinflammatory cytokines (IL-1β, IL-6, IL-17, RANTES) and chemokines (CCL2) (73).

Infliximab and adalimumab are biological TNFα inhibitors approved for treating inflammatory disorders such as Crohn’s disease, ulcerative colitis, rheumatoid arthritis, plaque psoriasis, and uveitis (125, 135). By lowering the expression of TNFR1 and caspase-3 activity, infliximab alleviated retinal degeneration induced by PDE6 inhibition in cultured porcine retina (74, 127). Adalimumab administered intraperitoneally or topically improved PR survival while decreasing microglial activation and reactive gliosis in the rd10 retina. Inhibition of PARP and RIPK signaling, as well as NLRP3 inflammasome assembly, are mechanisms involved in this protective response (25, 75).

2.1.3 Protective effects of TNF signaling

Notably, TNFα KO retinas tend to express both pro- and anti-inflammatory factors at reduced levels when compared with controls (73), implying that removing TNFα would also damage the immune system’s defenses. Recent work by Kuhn et al. established that TNFα, in collaboration with TNFR1, TNFR2, and p75NTR, induces signals that are indispensable for neural development and that disturbances to TNFR family signaling result in unhealthy axonal development (136).

ADAM17 regulates the expression of TNFα as well as the receptor TNFR (124). Muliyil et al. reported that ADAM17 and soluble TNF mediate a novel cytoprotective pathway in Drosophila. Loss of ADAM17 or TNF/TNFR signaling drives the accumulation of lipid droplets and degeneration in the Drosophila retina, whereas restoration of ADAM17 or TNF/TNFR in glia is sufficient to rescue the degeneration phenotype. TNF and TNFR are explicitly needed in glia; loss of either in glia, but not neurons, leads to the accumulation of lipid droplets. Furthermore, inactivation of ADAM17 in human iPSC-derived microglia similarly induces aberrant lipid droplet accumulation and mitochondrial reactive oxygen species generation (137), indicating that comparable processes in which TNF works not as an inflammatory trigger but as a trophic survival factor (137) may also be involved in the mammalian retina.

Benoot et al. evaluated the numerous contradictory findings of TNFα application in lung cancer (138), bringing to our awareness the varied functions of various TNF family members and the positive impacts of TNF signaling. Modern genomic, transcriptomic, and proteomic techniques are useful for identifying signaling events and molecules in signal transduction (139, 140). Tanzer et al. (141) discussed in detail how modern proteomic approaches offer a novel perspective on TNF signaling.

Currently, the precise mechanisms of TNFα synthesis remain obscure. Future investigation of TNFα signaling requires the power of new technology, and the potential protective function of TNFα merits greater consideration.

2.1.4 TNFα and microglia-Müller glia interaction

Müller glia exposed to activated microglia modify the expression of a variety of signaling molecules, including (1) elevation of growth factors such as GDNF and leukemia inhibitory factor (LIF), (2) enhanced proinflammatory factor production, and (3) overexpression of chemokines and adhesion proteins (142). TNFα is the most prevalent cytokine produced by reactive microglia, and it stimulates LIF expression in Müller glia in a p38MAPK-dependent manner. Inhibition of p38 MAPK activity lowered LIF expression and accelerated PR mortality in light-damaged retinas (143), similar to previous reports that TNFα prevents cell death by activating the JAK/STAT3 pathway through the IL-6 receptor (144). When TNFα stimuli engage previously activated Müller glia, however, inducible cytokines consisting of more proinflammatory cytokines (TNFα, iNOS, IL-6) and less LIF are produced (145). In other words, depending on the type and degree of stimuli, Müller glia activation generates both neuroprotective and proinflammatory responses, and Müller glia under continuous stimulation are likely to exhibit a detrimental phenotype.

2.2 TLR signaling

Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) responsible for identifying pathogen-associated molecular patterns (PAMPs) and DAMPs and mediating immune responses; the generation of PAMPs or DAMPs prompts pathogen invasion or tissue injury. TLR expression is conserved among species, and to date, 10 TLRs (TLR1–10) in humans and 12 TLRs (TLR1–9 and TLR11–13) in mice have been described. TLRs are predominantly but not exclusively expressed on immune cells (146–148).

TLRs serve as the first line of defense for the innate immune system. Upon recognition of DAMPs or PAMPs, TLRs dimerize and initiate recruitment of Toll/IL-1 receptor (TIR) domain-containing adaptor molecules, including myeloid differentiation primary response 88 (MyD88), TIR-domain-containing adaptor-inducing interferon-β (TRIF), MyD88 adaptor-like protein (Mal), and TRIF-related adaptor molecule (TRAM), thereby initiating intracellular signaling cascades: the MyD88- or TRIF-dependent pathways (146). TLR activation facilitates the transduction of NF-κB and MAPK (149–151), as well as the release of proinflammatory cytokines (TNFα, IL-6, IL-1β, and IFNβ), chemokines, and cluster of differentiation 80 (CD80), CD86, CD40, and major histocompatibility complex class II (146).

Activation of TLR signaling has been shown to worsen inflammation and accelerate the course of RP (77, 152, 153). Microglia highly express TLRs (154), and TLR activation in the retina facilitates microglial activation and infiltration (77, 155). Moreover, microglia in the rd1 retina undergo RIP1/RIP3-dependent necroptosis mediated by TLR4 activation, which amplifies retinal inflammation and destruction with large amounts of proinflammatory cytokines (TNFα and CCL2) (152).

2.2.1 DAMPs activate TLRs in RP

High-mobility group box-1 (HMGB1) is a proinflammatory factor and DAMP released by dying cells or activated macrophages that mediates the immune response via PRRs (156–158). HMGB1 stimulates an inflammatory response in diabetic retinopathy through TLR4/NF-κB signaling (159).

Increased levels of HMGB1 were detected in the vitreous of patients with RP, along with the presence of necrotic enlarged cone cells (53). In cultured cone-like 661W cells, recombinant HMGB1 treatment induces apoptosis and upregulates the expression of IL-6 and TNFα (160), and external HMGB1 induces retinal ganglion cell death via TLR2/4 signaling (161), whereas HMGB1 inhibition or neutralization attenuates the inflammatory response and promotes retinal neuron survival (162, 163).

2.2.2 TLR blockade

Upregulation of Tlr2, Il1b, Myd88 and Tirap was found in RP model rd10 and P23H mice, demonstrating TLR activation involvement in RP-associated retinal degeneration. Genetic deletion of TLR2 alleviated PR loss and vision impairment in both models (76). Similarly, in a light-induced retinal degeneration model, genetic TLR4 deletion reduced retinal inflammation and degeneration (77). Minocycline is an effective microglial inhibitor. In inherited and induced RP models, minocycline administration decreased microglial infiltration and proinflammatory molecule expression and promoted PR survival and functional retention (78–82). Minocycline treatment suppresses MAPK and NF-κB signaling in LPS-stimulated microglia (164), and it has been ascertained that minocycline prevents microglial activation by inhibiting TLR2 (165, 166) and TLR4 (167) signaling.

2.2.3 MyD88

Most TLRs (except for TLR3) use MyD88 as a downstream adaptor protein; moreover, MyD88 is a component of the IL-1R signaling cascade (168, 169). MyD88 features a death domain and a TIR domain. Upon TLR/IL-1R ligation, MyD88 is recruited to the receptor and interacts with IRAK2/4 through their death domains, which activates NF-κB, activator protein-1, and interferon regulatory factors (169).

MyD88 KO mice display attenuated immune responses and are unable to produce normal levels of inflammatory cytokines (170). This diminished immune response preserved PR survival and retinal function during degeneration in rd1 mice lacking MyD88 (83). Similarly, pharmacologic inhibition of MyD88 in rd10 mice with MyD88 inhibitor peptide reduced PR apoptosis and improved rod-related function; treatment also lowered the number of microglia in the PR layer and increased microglia/macrophage expression of the neuroprotective marker Arg1 (84). Further proteomic analysis demonstrated that treatment with such MyD88 inhibitor peptides boosted crystalline expression, suggesting that MyD88 inhibition may also enhance intrinsic tissue-protective mechanisms (85).

2.2.4 AMWAP

Activated microglia/macrophage WAP domain protein (AMWAP), secreted by reactive microglia, is a hallmark of microglial activation. While AMWAP overexpression in microglia lowers the production of proinflammatory factors such as IL-6, iNOS, CCL2, CASP11, and TNFα, extracellular AMWAP endocytosed by microglia inhibits TLR2- and TLR4-induced NF-κB translocation by preventing IRAK-1 and IκBα proteolysis (86). AMWAP administration lowers the apoptosis of 661w cone-like cells treated with microglia-conditioned medium (86), indicating that AMWAP is a potential self-modulator of TLR signaling in microglia.

The TLR signaling pathway plays a fundamental role in inflammatory and immune responses. Molecules released from injured neurons induce an intracellular signaling cascade through TLR/MyD88, contributing to further retinal damage. Blockage of TLR/MyD88 alleviates RP by reducing inflammatory responses and enhancing protective effects.

2.3 NLRP3 inflammasome activation

Inflammasomes are cytosolic multiprotein complexes that facilitate the release of mature IL-1β, IL-18, and cleaved caspase-1. The intracellular PRRs, NOD-like receptors (NLRs), are important components of the inflammasome complex. Some NLRs oligomerize upon activation to form multiprotein complexes that function as caspase-1-activating scaffolds (171). NLRP3 is the most well-studied NLR; NLRP3 inflammasome assembly requires two signals: a priming signal that activates NF-κB, followed by transcription of NLRP3, pro-IL-1β, and pro-IL-18. A second activation signal facilitates the recruitment and oligomerization of NLRP3, adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and pro-caspase-1. Once the inflammasome is assembled, it stimulates pro-caspase-1 self-cleavage and activation, and cleaved caspase-1 catalyzes pro-IL-1β and pro-IL-18 maturation and induces the release of their mature forms. The recognition of DAMPs or PAMPs that act through PRRs such as TLRs or cytokines that act through particular receptors (TNFR, IL-1R) exemplifies the priming signal. The activation signal encompasses a wide range of stimuli, including ion flux (K+, Cl-, Ca2+), lysosomal instability, mitochondrial dysfunction, reactive oxygen species generation, and trans-Golgi disassembly, with K+ efflux being the upstream event in almost all NLRP3 activations (172, 173).

Inflammasome activation initiates the host’s defense response to endogenous or external damaging stimuli and aids in homeostasis maintenance. Nevertheless, chronic inflammasome activation and the subsequent overproduction of caspase-1, IL-1β, and IL-18 can be detrimental.

Canine models of RP upregulate NLRP3 inflammasome-related genes (26). NLRP3 was detected in cone PRs and one-third of reactive microglia in P23H rhodopsin mutant retinas, which also upregulates the expression of mature IL-1β and IL-18, as well as cleaved caspase-1, indicating inflammasome activation during retinal degeneration. In rd10 mice, administration of the antioxidant N-acetylcysteine prevented PR loss and suppressed inflammatory factors and microglial activation (24). Studies conducted on P23H mice demonstrated that N-acetylcysteine lowered NLRP3 expression by 50% and decreased microglial infiltration, hence improving cone survival and retinal function (87).

2.3.1 P2X7R

The purinergic receptor P2X7R is an adenosine triphosphate (ATP)-gated ion channel and a well-known inflammasome activator that can enhance the expression of the NLRP3 inflammasome in microglia (174). By inducing K+ efflux, ATP-mediated P2X7R activation promotes NLRP3 inflammasome activation (173).

ATP is abundant in PRs as an energy source and neurotransmitter. During retinal degeneration, ATP leaches from dying PRs and activates P2X7R (175). Intravitreal injection of PPADS (pyridoxal-phosphate-6-azophenyl-2’,4’-disulfonic acid), a purinergic antagonist, lowers PR loss in rd1 mice (88). In contrast, intravitreal administration of ATP to WT (wild-type) retinas induces PR degeneration similar to that in the P23H RP model (176), whereas treatment with the selective P2X7R inhibitor BBG (Brilliant Blue G) protects against this ATP-mediated PR apoptosis (177). BBG therapy also reduced inflammasome components (NLRP3, cleaved caspase-1 and mature IL-1β proteins) in P23H retinas (87).

In the absence of extracellular ATP, P2X7R functions as a scavenger receptor that governs microglial clearance of extracellular debris, whereas P2X7R overactivation triggers NLRP3 inflammasome activation by provoking lysosomal instability. Lowering extracellular ATP levels may have the dual benefit of enhancing phagocytosis while decreasing inflammation (178).

2.3.2 IL-1β

IL-1β is a key product of NLRP3 inflammasome activation and a potent immunomodulation factor that orchestrates inflammatory and host defense responses (172, 179). IL-1β signals through IL-1R1. IL-1β binding to IL-1R1 stimulates pathways such as NF-κB, p38, JNKs, ERKs, and MAPKs, facilitating inflammatory cell recruitment and local/systemic inflammatory responses (180). Appropriate IL-1β/IL-1R1 signaling is required for a host’s defensive response to infections, whereas excessive IL-1β signaling is seen in a variety of hereditary and nonhereditary autoinflammatory disorders. IL-1β activity is endogenously regulated by IL-1R2 and IL-1Ra; IL-1R2 is a decoy receptor that sequesters the IL-1β signal, while IL-1Ra blocks IL-1β by competitively binding to IL-1R1 (180).

Intravitreal delivery of exogenous IL-1β triggered an immediate inflammatory response in the retina, including leukocyte recruitment and BRB destruction (181). However, IL-1β does not trigger PR death directly, as IL-1R1 expression is low in PRs. Through IL-1R1 expressed on Müller glia, IL-1β drives glutamate excitotoxicity-induced rod PR loss. The IL-1β/IL-1R1 signal disrupts the process of glutamate conversion into glutamine in Müller glia, resulting in an increased intracellular glutamate concentration, and upregulates xCT (the core subunit of the cystine/glutamate transporter system xc-) expression, which facilitates glutamate release into the extracellular space. Furthermore, IL-1β upregulates the expression of the ionotropic glutamate receptor in retinal neurons, which may increase neuronal vulnerability to glutamate excitotoxicity (182). Infiltrating microglia in the rd10 retina upregulate the expression of IL-1β (19) and block IL-1β signaling using anakinra, a commercially available recombinant IL-1Ra that is fully active in blocking IL-1R1 (183), which reduces PR apoptosis and preserves outer nuclear layer thickness in rd10 animals (19). In contrast, Todd et al. (184) demonstrated that IL-1β expressed by reactive microglia provides neuroprotection via IL-1R1 expressed on astrocytes in another mouse model of NMDA-induced retinal degeneration. Despite the use of different models, we were able to determine that IL-1β acts on the surface receptors of distinct glial cells and has varying effects on PR survival.

2.4 Chemokine signaling

2.4.1 CX3CL1/CX3CR1

CX3CR1 expression in the central nervous system (CNS) is considered to be restricted to microglia, and the expression of its sole ligand, CX3CL1 (also known as fractalkine), is confined to certain neurons (185). CX3CL1/CX3CR1 signaling facilitates the interaction between neurons and glia and plays a vital role in CNS neuroinflammation (186, 187).

CX3CL1/CX3CR1 signaling contributes to normal microglial and PR function. CX3CR1 signaling governs the dynamic activity of retinal microglia (188). Microglial ablation and repopulation in the mouse retina have shown that microglial recruitment is regulated by CX3CL1/CX3CR1 signaling (40), and Müller glia augment microglial migration and infiltration by increasing CX3CL1 secretion and microglial CX3CR1 expression (68). In addition, CX3CR1 signaling is required for retinal neuron growth, as CX3CR1-deficient retinas have shorter outer segments and diminished cone-related retinal function (189).

CX3CL1/CX3CR1 signaling affects microglial homeostasis by modulating the inflammatory response and phagocytosis. Increasing CX3CL1/CX3CR1 signaling in RP retinas could be beneficial. CX3CR1 deficiency impairs microglial phagocytic clearance of neurotoxic species. Reportedly, CX3CL1 signaling enhances microglial erythrophagocytosis through the CD163/HO-1 axis (190), whereas CX3CR1 KO weakens microglial phagocytosis to β-amyloid and mediates lysosomal dysfunction, resulting in an escalation of neuroinflammation due to β-amyloid accumulation (191).

CX3CR1 deficiency enhances the inflammatory response of microglia. CX3CR1-deficient microglia exhibit greater neurotoxicity (192), and CX3CR1-deficient microglia have an elevated amount of surface P2X7R, which increases IL-1β maturation and release (193). CX3CR1 deletion in microglia-like cells generated from human iPSCs induced enhanced inflammatory responses to LPS stimuli and phagocytic activity to fluorescent beads (194). Loss of CX3CR1 signaling in young animals resulted in a microglial transcriptome similar to that of aged mice, with dysregulated expression of genes related to immune function (195).

CX3CL1 expression is downregulated in rd10 retina before the onset of primary rod degeneration (196), and CX3CR1 KO in rd10 mice increases microglial infiltration and phagocytosis, as well as the generation of pro-inflammatory cytokines, which accelerates PR loss (82, 89), whereas exogenous CX3CL1 supplementation preserves morphology and function (89). CX3CL1 has been shown to deactivate microglia by blocking the NF-κB pathway and activating the Nrf2 pathway (197). A norgestrel-supplemented diet protected rd10 retinas from PR degeneration, and this protection was achieved by the upregulation of CX3CL1/CX3CR1 signaling and the reduction of proinflammatory cytokine production (91, 92).

Recent work by Wang et al. demonstrated that overexpression of soluble CX3CL1 via AAV8 prolongs cone survival and improves cone-related visual function in RP model rd1 and rd10 mice. This therapeutic effect is restricted to cone PRs, has no effect on microglial activity or inflammatory factor levels and is not even dependent on the presence of a normal number of microglia (90). In light of this, further research is needed to determine whether CX3CL1 action in the retina is limited to microglia or whether other pathways exist.

2.4.2 CCL2/CCR2

Part of the evidence suggests that CCL2/CCR2 signaling is detrimental, as inhibition of CCL2/CCR2 signaling attenuates microglial activity and degeneration in RP (95–97). CCL2 is highly expressed by stressed PRs, activated microglia, and Müller glia in degenerating retina (95, 198, 199). By binding to its receptor, CCR2, which is expressed on peripheral mononuclear phagocytes, mediates the influx of circulating monocytes into inflamed retinas (200). Using fluorescent protein-labeled Mertk ^(-/-) Cx3cr1 ^(GFP/+) Ccr2 ^(RFP/+) mice, Kohno H and colleagues demonstrated that both minocycline and lecithin-bound iodine (LBI) ameliorate PR death by inhibiting CCL2/CCR2 signaling (93, 94). Meanwhile, constitutive expression of CX3CR1 in the retina represses CCL2 expression and the recruitment of neurotoxic inflammatory CCR2+ monocytes (201).

However, there is evidence that CCL2 signaling may have a protective role in the degradation of RP. In a light-induced mouse model of degeneration, blocking CCL2/CCR2 signaling decreased infiltrating monocytes but had no effect on the rate of retinal thinning (198). Alde-Low EPCs (low aldehyde dehydrogenase activity endothelial progenitor cells) transplantation therapy rescued vasculature and PRs in rd1 mice, and CCL2 secreted by Alde-Low EPCs recruited a subpopulation of monocyte-derived macrophages that highly expressed CCR2 and the neuroprotective factors TGF-β, IGF-1 and IL-10 (202). In brief, induction of CCL2 expression by Alde-Low EPCs in rd1 retinas resulted in the recruitment of neuroprotective macrophages.

It is apparent that CCL2/CCR2 signaling mediates the recruitment of monocyte-derived macrophages in the degenerating retina, but it remains to be determined whether these recruited cells are beneficial or detrimental.

2.5 JAK/STAT signaling

The JAK/STAT signaling pathway is a ubiquitously expressed intracellular signal transduction system implicated in a wide range of biological functions. Various ligands, including cytokines, growth hormones, growth factors, and their receptors, can activate the JAK/STAT pathway (203). Briefly, ligand binding to specific receptors induces receptor multimerization and JAK activation, activated JAKs phosphorylate the receptors, activate and phosphorylate their primary substrate STAT, and phosphorylated STAT dimerizes and translocates into the nucleus, where it binds to particular regions to either activate or inhibit the transcription of target genes. Suppressor of cytokine signaling (SOCS) is a negative modulator of JAK/STAT signaling, and its expression is promoted by stimulation of JAK/STAT signaling (203, 204). Numerous studies on the JAK/STAT pathway have revealed its significance in neoplastic and inflammatory disorders (203, 205).

2.5.1 JAK/STAT and microglia-associated inflammation

Expression and activation of STAT proteins are implicated in the plasticity of the retina during embryonic and postnatal stages (206), and mice deficient in SOCS1/STAT1 develop severe ocular illnesses with massive inflammatory cell infiltration (207). STAT signaling plays a central role in the degeneration of the rd10 retina, as evidenced by proteomic profiling (208). Furthermore, activation of JAK/STAT signaling was also observed in the retinas of light-induced and inherited (rd1 and VPP mouse) RP animal models (98, 209).

AG490 is a JAK2-specific inhibitor that suppresses microglial activation and the production of inflammatory factors such as TNFα and IL-6 by reducing STAT3 phosphorylation (210). AG490 induces M2-type microglial polarization by blocking JAK2/STAT3 signaling in acute paraquat exposure-induced microglial activation (211). In light-damaged retinas, AG490 treatment decreased JAK and STAT phosphorylation as well as PR apoptosis (98).

Olfactory ensheathing cell (OEC) transplantation improved retinal function in RCS rats. OEC treatment dramatically reduced active resident microglia/infiltrated macrophages and the release of proinflammatory cytokines while increasing anti-inflammatory cytokines in the transplantation area. This neuroprotection appears to be mediated in part by increased SOCS3 expression and decreased JAK2/STAT3 activity. Coculture of OECs with the BV2 microglial cell line revealed a shift in microglial cytokine release toward an anti-inflammatory pattern (99). According to the literature, SOCS3-deficient microglia display increased phagocytic activity (212), whereas elevated SOCS3 expression in microglia decreases GM-CSF/IFN-γ-driven inflammatory responses by blocking the activities of JAK1 and JAK2 through its KIR domain (213). In addition, increasing SOCS1 signaling with SOCS1-KIR, a SOCS1 mimetic peptide, suppressed the recruitment of inflammatory cells into the retina and stimulated IL-10 production (214).

Multiple jakinibs (JAK inhibitors) are approved for the clinical management of malignancy, rheumatic, lymphoproliferative, and inflammatory diseases, and most recently, coronavirus disease 2019 (205), but their efficacy in the treatment of RP has not been evaluated.

2.5.2 JAK/STAT and Müller glial neuroprotection

Activation of JAK/STAT signaling has a protective effect on the RP retina. pMSC-derived retinal progenitor cell transplantation increased PR preservation in rd12 mice, and this protection was partially mediated by activation of the JAK/STAT pathway (100).

Application of ciliary neurotrophic factor (CNTF) in RP preclinical research has gained significant neuroprotection and has been employed in clinical trials (101, 215, 216).. CNTF therapy enhances the protective properties of Müller glia through LIF/gp130/STAT3 signaling, thereby preventing retinal degeneration. CNTF treatment elevates the expression of LIF and endothelin 2 (Edn2) (102), and LIF is essential for CNTF-elicited STAT3 activation (217). LIF belongs to the IL-6 cytokine family and signals through the gp130 receptor. In a mouse model of light-induced retinal degeneration, intravitreal delivery of LIF improved PR survival and retinal function by activating STAT3 in Müller glia and PR (103). Stressed PRs secrete signal molecules such as Edn2 and H2O2 that facilitate LIF induction in Müller glia; Edn2 triggers LIF transduction by binding to endothelin receptor B (Ednrb) localized to Müller glia; and H2O2 increases LIF transcript levels by stabilizing LIF mRNA via ILF3 (interleukin enhancer binding factor 3) (98, 218–220). LIF deficiency or Ednrb antagonism diminishes JAK/STAT activation and the amount of reactive Müller glia, resulting in accelerated degeneration; in contrast, LIF supplementation or Ednrb agonism improves PR survival in degenerating retina (218, 221).

Deletion of gp130 in either Müller glia or rod PRs severely dampened the activation of CNTF-triggered signaling as well as PR rescue (102), and when Müller glia were ablated, LIF no longer provided protection (222). However, other research suggests that gp130 deficiency in Müller glia decreases STAT3 phosphorylation but does not weaken the neuroprotection of exogenous LIF (223) because gp130 activation in PR presumably mediates a cell-autonomous protective mechanism with a general protective role independent of pathological stimulus (223, 224).

Modulation of JAK/STAT signaling results in contrary immunomodulatory effects in different retinal components. On the one hand, inhibition of JAK2/STAT3 in microglia contributes to inflammation mitigation. On the other hand, LIF-induced STAT3 signaling in Müller glia favors neuroprotection, which seems to be an endogenous protective mechanism. We speculate that this paradoxical outcome involves crosstalk between retinal microglia and Müller glia, which is not yet fully understood. Phosphorylated JAK also activates PI3K, so there may be synergy between JAK/STAT signaling and other pathways.

3 Epigenetic modulation in inflammation suppression

Epigenetic modifications, which include DNA methylation, histone modification, and noncoding RNAs, refer to changes in gene expression patterns without altering the genomic DNA sequence (225). Epigenetic modifications are implicated in aspects of individual growth and disease development, including gene expression, cell proliferation and differentiation, misfolded protein response, and cytoskeletal dynamics (226). Although the concept of curing diseases through epigenetic regulation is relatively new, it has demonstrated considerable therapeutic potential in research on cancer, autoimmune diseases, endocrine diseases, congenital disease and many others (227, 228). Epigenetic changes contribute to the development of RP, and remarkable progress has been made in the treatment of RP with epigenetic modification therapies.

3.1 Histone acetylation and methylation

Histone acetylation and methylation are the two most well-studied types of histone modification, with acetylation typically resulting in increased gene expression and methylation being related to either increased or decreased gene transcription. Histone acetylation is regulated by histone acetyltransferases and histone deacetylases (HDACs), while histone methylation is regulated by lysine methyltransferases and arginine methyltransferases and histone demethylation by histone demethylases. Enzymes that add or remove epigenetic marks on histones are known as “writers” and “erasers.” In addition, there are “readers” containing bromodomains, chromodomains, or Tudor domains that are able to decipher histone codes (229).

RP retinas exhibit excessive HDAC activity (104, 105, 230), and HDAC inhibition delays retinal degeneration in RP animal models (rd1 and rd10 mice and zebrafish) (104–107). In rd10 mice, the HDAC inhibitor romidepsin prevented rod degeneration and enhanced retinal function. Two molecular mechanisms contribute to this neuroprotective effect. First, by acting on histone targets in PRs, increasing chromatin accessibility and upregulating neuroprotective genes, and second, by acting on nonhistone targets in microglia and resident and invading immune cells, it suppresses inflammatory gene transcription and inflammation (108).

Microglial activity is related to histone methylation levels. LPS-activated microglia increase HDAC expression, which is accompanied by an increase in inflammatory gene expression (231). HDAC inhibition or knockdown promotes a protective microglial phenotype and reduces neuroinflammation (232–234).

Valproic acid is an HDAC inhibitor that reduces PR degeneration in rd1 and P23H RP models (109, 110). Valproic acid increases the expression of STAT1 by inhibiting HDAC3 expression; subsequently, acetylated STAT1 forms a complex with nuclear NF-κB p65, preventing NF-κB p65 DNA-binding activity (235).

Moreover, suppression of the “read” (bind) behavior to histone acetylation marks of bromodomain and extraterminal domain proteins by JQ1 ameliorated PR degeneration and maintained electroretinographic function in rd10 mice. This protection seems to be partially mediated by the inhibition of retinal microglial proliferation, migration, and cytokine production (111).

Several studies, including our previous report, have reported altered histone methylation in RP retinas (112, 236, 237). Lysine demethylase 1 inhibition attenuated PR degeneration in rd10 mice, in part by inhibiting microglial-related inflammation (108). DZNep (3-deazaneplanocin A) specifically inhibits Ezh2 (H3K27 trimethyltransferase) and mediates neuroprotective effects in rd1 mice by inhibiting H3K27me3 deposition (112). Ezh2 reportedly mediates TLR-induced inflammatory gene expression (238) and activation of multiple types of inflammasomes in microglia (239), hence promoting microglial-related pathologies.

3.2 MicroRNA

MicroRNAs (miRNAs) are small noncoding RNAs that modify gene expression post-transcriptionally by targeting messenger RNAs, long noncoding RNAs, and pseudogenes and circular RNAs. MiRNAs can be packed into exosomes or microvesicles to perform long-distance cell-to-cell communication. MiRNAs play a critical role in gene expression modulation and are therefore interesting candidates for the development of biomarkers and therapeutic targets (240). Throughout development, miRNAs are required for retinal neuron differentiation (241, 242). Dysregulated miRNAs were found in the retinas of mouse and canine models of RP (243, 244), indicating the involvement of miRNAs in the etiology of RP.

MiRNAs regulate microglial phenotypes, as evidenced by various studies on retinal and neurodegenerative disorders (245, 246). Inhibition of miR-6937-5p preserved the outer nuclear layer thickness and promoted the ERG wave response in rd10 mice (113), and AAV-miR-204 attenuated retinal degeneration in two different mouse models. By downregulating microglial activation and PR mortality, miR-204 alters the expression profiles of transgenic retinas toward those of healthy retinas (114). In addition, miR-223 is required for the regulation of microglial inflammation and the maintenance of normal retinal function (247).

3.3 DNA methylation and trained immunity: Epigenetic reprogramming of immunity phenotype

DNA methylation refers to the addition of a methyl group to the 5′-carbon of a cytosine (C) ring, resulting in the formation of 5-methylcytosine (5mC), which mainly occurs in the promoter regions. Typically, methylation modifications result in gene repression, and global genomic hypermethylation relates to heterochromatin formation and inhibits transcription (248). Aberrant regulation of DNA methylation results in PR degeneration and neuronal loss in the retina. In the absence of DNA methyltransferase 1, the initiation of PR differentiation is severely hindered (249). In RP retinas, binding sites of several important transcription factors for retinal physiology were hypermethylated (250). The role of DNA methylation in the development of retinitis pigmentosa has been reviewed in detail elsewhere (251) and will not be repeated here.

We argue that trained immunity regulates the microglial phenotype in RP by plasticizing microglial reactivity via epigenetic modification.

Trained immunity, also known as innate immune memory, refers to the phenomenon in which innate immunity modifies its function after an initial insult and reacts more vigorously to subsequent stimuli. Epigenic reprogramming determines the immune phenotype of immune cells and leads to long-lasting functional alterations (252, 253) (Figure 2). Using macrophages as an illustration, in the resting state, the promoter regions of inflammatory genes are enriched with repressive epigenetic marks, called epigenetic barriers, to prevent activation in the absence of stimuli. Upon stimulus, repressive epigenetic marks are removed, and activating epigenetic marks are introduced to the promoters and enhancers of specific genes in an attempt to encourage inflammatory molecule synthesis and phagocytosis to eliminate the insult. After stimulus elimination, activating epigenetic marks are partly retained (254). The innate immune system may become overly trained in chronic inflammatory diseases as a result of such mechanisms, resulting in pathological tissue damage.

Figure 2

In the context of neurodegenerative disorders of the CNS, the relationship between trained immunity and microglial phenotype has been discussed (255, 256). Low-dose LPS intraperitoneally administered to mice induced long-lasting innate immune memory in brain microglia and exacerbated Alzheimer’s disease pathology. Activated microglia are enriched with the epigenetic marks H3K4me1 and H3K27ac, which define active enhancers (256). In RP model P23H rats, intraperitoneal injection of low-dose LPS increased microglial activation and the number of infiltrating microglia, as well as elevated the expression levels of several inflammation-related genes (257). In addition to the activation of retinal microglia, elevated levels of serum cytokines show the activation of peripheral immune cells in RP (22, 23). Recent work by Su et al. revealed that monocytes from patients with autosomal recessive RP exhibit a trained-like phenotype. Upon stimulation, these monocytes produce more TNF-α, IL-6, and IL-1β and upregulate inflammatory pathways such as NF-κB (258). Current evidence supports a role for trained immunity in RP pathogenesis by epigenetic reprogramming of microglia and peripheral macrophages to modulate the immune phenotype and trigger an active immune response, although many details remain to be confirmed.

4 Gut microbiome and microglial activity

The gut microbiome, which resides in the intestinal tract and performs nutrition metabolism, has recently been found to influence the maturation of the immune system. Components and metabolites of microbial cells engage in the modulation of immune recognition and immune tolerance through innate immune receptors on intestinal epithelial cells and influence the function of innate myeloid cells and lymphoid cells through diverse mechanisms (Figure 3). In addition, the microbiota’s make-up and function are subject to the innate immune system. Therefore, gut dysbiosis may induce immune system dysregulation and trigger disease emergence (259).

Figure 3

The gut microbiome has been linked to retinal degenerative disorders such as age-related macular degeneration (260) and diabetic retinopathy (261). Using the rd10 RP mouse model, Kutsyr O. et al. (262) related alterations in the composition profiles of the gut microbiome to RP. Compared to healthy mice, the gut microbiome of rd10 mice had reduced ASV richness and α diversity. Rd10 mice, in particular, feature a high proportion of B. caecimuris, a species that is uncommon in healthy gut mice, but lack four species (Rikenella spp., Muribaculaceace spp., Prevotellaceae UCG-001 spp., and Bacilli spp.) that are common in the healthy gut microbiome (262). The gut microbiome is susceptible to dietary influences. Further research by the same group demonstrated that a short-term high-fat diet significantly modifies the gut flora, enhances retinal oxidative stress and inflammation, and ultimately accelerates the degeneration of the rd10 retina (263). Thus, dysbiosis in the gut contributes to retinal inflammation and constitutes the pathogenesis of RP.

By exchanging the intestinal microbiota (Fecal microbiota transplant, FMT) of young and aged mice, emerging evidence by Parker et al. (264) suggests that the gut microbiome is a modifier of retinal inflammation. Compared to young mice, aged mice exhibit increased systemic and tissue inflammation, as evidenced by elevated serum proinflammatory cytokines (TNFα, IL-6), microglial overactivation in the brain, and C3 accumulation at the RPE/Britch’s membrane interface. Transferring aged donor microbiota to young mice disrupts the intestinal epithelial barrier and triggers inflammation in the retina and brain, whereas transfer of aged mice with young donor microbiota could reverse age-related inflammation (264).

The evidence above supports the “diet-gut microbiome-retina axis” hypothesis in the pathogenesis of RP. Despite the fact that this work is still in its early stages, the gut microbiota is a promising therapeutic target for RP.

5 Herbal agents in inflammation suppression

Herbal compounds, or phytochemicals derived from plants, possess a wide range of biological activities and have been explored for the treatment of RP, demonstrating anti-inflammatory properties in RP investigations.

Curcumin is a polyphenolic compound produced from the spice turmeric. Curcumin provided morphological and functional protection in rd1 mice, P23H rats, and an MNU-induced RP model (115, 116, 265, 266). A single vitreous injection of curcumin reduced PR loss in rd1 mice by inhibiting microglial activation and modulating the expression of CCL2, TIMP-1 and VCAM-1 (115).

Lyceum barbarum polysaccharides and zeaxanthin dipalmitate are two main bioactive agents extracted from wolfberry. Lyceum barbarum polysaccharides protects against retinal degeneration by modifying inflammation and apoptosis through the inhibition of NF-κB and HIF-1α expression (117, 118). zeaxanthin dipalmitate acts through several pathways, including STAT3, CCL2 and MAPK, in parallel to inhibiting inflammation in the rd10 retina (119).

Saffron, widely used in traditional Chinese medicine for its anti-inflammatory and antioxidant properties, protects PRs exposed to environmental ATP by blocking P2X7R signaling (120). In P23H rats, saffron administration increased PR survival and functional retention while decreasing vascular disruption (121).

Resveratrol (3,40,5-trihydroxystilbene) is found in chocolate, fruits, and vegetables. Resveratrol treatment inhibited microglia-mediated death of 661W cells via downregulation of microglial migratory, phagocytic, and proinflammatory cytokine production (122). Subretinal injection of JC19 (3,4’-diglucosyl resveratrol), a resveratrol prodrug, reduced PR loss and improved functional performance in ERG tests of the rd10 retina. The author speculates that sirtuin1 activation is the underlying mechanism (123).

6 Conclusion and future perspectives

A large body of research conducted on the inflammatory processes during RP tries to discover common mechanisms that target multiple RP genotypes and develop appropriate therapeutic options. However, after reviewing the existing literature, we discovered that no single treatment is appropriate for all types of RP, and the application of valproic acid is a prime example, with treatment effects significantly varying between models with different genetic backgrounds and even exhibiting detrimental effects. This raises the prospect that a link between genetics and RP inflammation needs more investigation. To date, genetic mutations remain the only identified risk factor for RP. Different permutations of inheritance pattern, genotype, and the number of mutations lead to variations in the phenotype and pathological progression of RP. Similarly, we anticipate that the multiple phenotypes of inflammatory activation in RP are closely related to the genetic background. Nevertheless, the relationship between genetic background and inflammation is currently unclear due to the lack of corresponding evidence.

Both RP patients and animal models have a more susceptible immune system and are prone to developing inflammation. This abnormal immune system may depend heavily on the genetic background. The gut microbiota play a critical role in the maturation of the innate immune system after birth, and trained immunity is implicated in this process; however, the influence of genetic background on the maturation of the immune system has not been investigated. Therefore, long-term clinical observation and family tracing of the RP population are necessary. What needs to be documented should include, but is not limited to, macroscopic clinical manifestations, structural and functional measurements, and monitoring of local and peripheral inflammation levels. And appropriate follow-up criteria need to be established to ensure consistency of measurements and to obtain usable information.

Inflammation is an important feature of RP, and the present review highlights the role of immunomodulation in RP treatment. There has been significant interest in modulating the inflammatory response as a strategy to treat RP, and an increasing number of studies have proven the effectiveness of immunomodulation in ameliorating and perhaps reversing retinal degeneration. Therapeutic strategies based on immunomodulation are a potential treatment for RP, and deepening the understanding of immune modulation is helpful in establishing suitable therapies. As with immunotherapies already carried out, artificial regulation of immunity will bring inevitable side effects. It is challenging to regulate immunity accurately and to enhance the beneficial effects and minimize the harmful ones concurrently. Many of these specific mechanisms need to be further studied, especially the interactions between these pathways.

Funding

This work was supported by grants from the Science and Technology Department of Sichuan Province (2020YFS0205).

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  DaigerSPSullivanLSBowneSJ. Genes and mutations causing retinitis pigmentosa. Clin Genet (2013) 84(2):132–41. doi: 10.1111/cge.12203

  • CrossRef
  • Google Scholar

• 2

  VerbakelSKvan HuetRACBoonCJFden HollanderAICollinRWJKlaverCCWet al. Non-syndromic retinitis pigmentosa. Prog In Retin Eye Res (2018) 66:157–86. doi: 10.1016/j.preteyeres.2018.03.005

  • CrossRef
  • Google Scholar

• 3

  HartongDTBersonELDryjaTP. Retinitis pigmentosa. Lancet (2006) 368(9549):1795–809. doi: 10.1016/S0140-6736(06)69740-7

  • CrossRef
  • Google Scholar

• 4

  BrinkmanCJPinckersAJBroekhuyseRM. Immune reactivity to different retinal antigens in patients suffering from retinitis pigmentosa. Invest Ophthalmol Vis Sci (1980) 19(7):743–50.

  • Google Scholar

• 5

  HerediaCDVichJMHuguetJGarcia-CalderonJVGarcia-CalderonPA. Altered cellular immunity and suppressor cell activity in patients with primary retinitis pigmentosa. Br J Ophthalmol (1981) 65(12):850–4. doi: 10.1136/bjo.65.12.850

  • CrossRef
  • Google Scholar

• 6

  YoshidaNIkedaYNotomiSIshikawaKMurakamiYHisatomiTet al. Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology (2013) 120(1):100–5. doi: 10.1016/j.ophtha.2012.07.006

  • CrossRef
  • Google Scholar

• 7

  MurakamiYYoshidaNIkedaYNakatakeSFujiwaraKNotomiSet al. Relationship between aqueous flare and visual function in retinitis pigmentosa. Am J Ophthalmol (2015) 159(5):958–63.e1. doi: 10.1016/j.ajo.2015.02.001

  • CrossRef
  • Google Scholar

• 8

  FujiwaraKIkedaYMurakamiYTachibanaTFunatsuJKoyanagiYet al. Aqueous flare and progression of visual field loss in patients with retinitis pigmentosa. Invest Ophthalmol Vis Sci (2020) 61(8):26. doi: 10.1167/iovs.61.8.26

  • CrossRef
  • Google Scholar

• 9

  FujiwaraKIkedaYMurakamiYNakatakeSTachibanaTYoshidaNet al. Association between aqueous flare and epiretinal membrane in retinitis pigmentosa. Invest Ophthalmol Vis Sci (2016) 57(10):4282–6. doi: 10.1167/iovs.16-19686

  • CrossRef
  • Google Scholar

• 10

  NishiguchiKMYokoyamaYKunikataHAbeTNakazawaT. Correlation between aqueous flare and residual visual field area in retinitis pigmentosa. Br J Ophthalmol (2019) 103(4):475–80. doi: 10.1136/bjophthalmol-2018-312225

  • CrossRef
  • Google Scholar

• 11

  NagasakaYItoYUenoSTerasakiH. Increased aqueous flare is associated with thickening of inner retinal layers in eyes with retinitis pigmentosa. Sci Rep (2016) 6:33921. doi: 10.1038/srep33921

  • CrossRef
  • Google Scholar

• 12

  StrobbeECelliniMFresinaMCamposEC. Et-1 plasma levels, aqueous flare, and choroidal thickness in patients with retinitis pigmentosa. J Ophthalmol (2015) 2015:292615. doi: 10.1155/2015/292615

  • CrossRef
  • Google Scholar

• 13

  KuchleMNguyenNXMartusPFreisslerKSchalnusR. Aqueous flare in retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol (1998) 236(6):426–33. doi: 10.1007/s004170050101

  • CrossRef
  • Google Scholar

• 14

  IvanovaEAlamNMPruskyGTSagdullaevBT. Blood-retina barrier failure and vision loss in neuron-specific degeneration. JCI Insight (2019) 5(8):e126747. doi: 10.1172/jci.insight.126747

  • CrossRef
  • Google Scholar

• 15

  NapoliDBiagioniMBilleriFDi MarcoBOrsiniNNovelliEet al. Retinal pigment epithelium remodeling in mouse models of retinitis pigmentosa. Int J Mol Sci (2021) 22(10):5381. doi: 10.3390/ijms22105381

  • CrossRef
  • Google Scholar

• 16

  VinoresSAKuchleMDerevjanikNLHendererJDMahlowJGreenWRet al. Blood-retinal barrier breakdown in retinitis pigmentosa: Light and electron microscopic immunolocalization. Histol Histopathol (1995) 10(4):913–23.

  • Google Scholar

• 17

  WangWKiniAWangYLiuTChenYVukmanicEet al. Metabolic deregulation of the blood-outer retinal barrier in retinitis pigmentosa. Cell Rep (2019) 28(5):1323–34.e4. doi: 10.1016/j.celrep.2019.06.093

  • CrossRef
  • Google Scholar

• 18

  GuptaNBrownKEMilamAH. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res (2003) 76(4):463–71. doi: 10.1016/S0014-4835(02)00332-9

  • CrossRef
  • Google Scholar

• 19

  ZhaoLZabelMKWangXMaWShahPFarissRNet al. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol Med (2015) 7(9):1179–97. doi: 10.15252/emmm.201505298

  • CrossRef
  • Google Scholar

• 20

  ten BergeJCFazilZvan den BornIWolfsRCWSchreursMWJDikWAet al. Intraocular cytokine profile and autoimmune reactions in retinitis pigmentosa, age-related macular degeneration, glaucoma and cataract. Acta Ophthalmol (2019) 97(2):185–92. doi: 10.1111/aos.13899

  • CrossRef
  • Google Scholar

• 21

  LuBYinHTangQWangWLuoCChenXet al. Multiple cytokine analyses of aqueous humor from the patients with retinitis pigmentosa. Cytokine (2020) 127:154943. doi: 10.1016/j.cyto.2019.154943

  • CrossRef
  • Google Scholar

• 22

  OkitaAMurakamiYShimokawaSFunatsuJFujiwaraKNakatakeSet al. Changes of serum inflammatory molecules and their relationships with visual function in retinitis pigmentosa. Invest Ophth Vis Sci (2020) 61(11):30. doi: 10.1167/iovs.61.11.30

  • CrossRef
  • Google Scholar

• 23

  McMurtreyJJ. Tso MOM. a review of the immunologic findings observed in retinitis pigmentosa. Surv Ophthalmol (2018) 63(6):769–81. doi: 10.1016/j.survophthal.2018.03.002

  • CrossRef
  • Google Scholar

• 24

  YoshidaNIkedaYNotomiSIshikawaKMurakamiYHisatomiTet al. Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology (2013) 120(1):E5–12. doi: 10.1016/j.ophtha.2012.07.008

  • CrossRef
  • Google Scholar

• 25

  de la CamaraCMFHernandez-PintoAMOlivares-GonzalezLCuevas-MartinCSanchez-AragoMHervasDet al. Adalimumab reduces photoreceptor cell death in a mouse model of retinal degeneration. Sci Rep (2015) 5:11764. doi: 10.1038/srep11764

  • CrossRef
  • Google Scholar

• 26

  AppelbaumTSantanaEAguirreGD. Strong upregulation of inflammatory genes accompanies photoreceptor demise in canine models of retinal degeneration. PloS One (2017) 12(5):e0177224. doi: 10.1371/journal.pone.0177224

  • CrossRef
  • Google Scholar

• 27

  RohrerBDemosCFriggRGrimmC. Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the Rd1 mouse. Exp Eye Res (2007) 84(1):82–91. doi: 10.1016/j.exer.2006.08.017

  • CrossRef
  • Google Scholar

• 28

  UrenPJLeeJTDoroudchiMMSmithADHorsagerA. A profile of transcriptomic changes in the Rd10 mouse model of retinitis pigmentosa. Mol Vis (2014) 20:1612–28.

  • Google Scholar

• 29

  ParkUCParkJHMaDJChoIHOhBLYuHG. A randomized paired-eye trial of intravitreal dexamethasone implant for cystoid macular edema in retinitis pigmentosa. Retina (2020) 40(7):1359–66. doi: 10.1097/IAE.0000000000002589

  • CrossRef
  • Google Scholar

• 30

  GlybinaIVKennedyAAshtonPAbramsGWIezziR. Photoreceptor neuroprotection in rcs rats Via low-dose intravitreal sustained-delivery of fluocinolone acetonide. Invest Ophthalmol Vis Sci (2009) 50(10):4847–57. doi: 10.1167/iovs.08-2831

  • CrossRef
  • Google Scholar

• 31

  GlybinaIVKennedyAAshtonPAbramsGWIezziR. Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats. Invest Ophthalmol Vis Sci (2010) 51(8):4243–52. doi: 10.1167/iovs.09-4492

  • CrossRef
  • Google Scholar

• 32

  IezziRGuruBRGlybinaIVMishraMKKennedyAKannanRM. Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. Biomaterials (2012) 33(3):979–88. doi: 10.1016/j.biomaterials.2011.10.010

  • CrossRef
  • Google Scholar

• 33

  GuadagniVBiagioniMNovelliEAretiniPMazzantiCMStrettoiE. Rescuing cones and daylight vision in retinitis pigmentosa mice. FASEB J (2019) 33(9):10177–92. doi: 10.1096/fj.201900414R

  • CrossRef
  • Google Scholar

• 34

  GinhouxFGreterMLeboeufMNandiSSeePGokhanSet al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science (2010) 330(6005):841–5. doi: 10.1126/science.1194637

  • CrossRef
  • Google Scholar

• 35

  O'KorenEGYuCKlingebornMWongAYWPriggeCLMathewRet al. Microglial function is distinct in different anatomical locations during retinal homeostasis and degeneration. Immunity (2019) 50(3):723–37.e7. doi: 10.1016/j.immuni.2019.02.007

  • CrossRef
  • Google Scholar

• 36

  Gomez PerdigueroEKlapprothKSchulzCBuschKAzzoniECrozetLet al. Tissue-resident macrophages originate from yolk-Sac-Derived erythro-myeloid progenitors. Nature (2015) 518(7540):547–51. doi: 10.1038/nature13989

  • CrossRef
  • Google Scholar

• 37

  HumeDAPerryVHGordonS. Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: Phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers. J Cell Biol (1983) 97(1):253–7. doi: 10.1083/jcb.97.1.253

  • CrossRef
  • Google Scholar

• 38

  SilvermanSMWongWT. Microglia in the retina: Roles in development, maturity, and disease. Annu Rev Vis Sci (2018) 4:45–77. doi: 10.1146/annurev-vision-091517-034425

  • CrossRef
  • Google Scholar

• 39

  DixonMAGreferathUFletcherELJoblingAI. The contribution of microglia to the development and maturation of the visual system. Front Cell Neurosci (2021) 15:659843. doi: 10.3389/fncel.2021.659843

  • CrossRef
  • Google Scholar

• 40

  ZhangYZhaoLWangXMaWLazereAQianHHet al. Repopulating retinal microglia restore endogenous organization and function under Cx3cl1-Cx3cr1 regulation. Sci Adv (2018) 4(3):eaap8492. doi: 10.1126/sciadv.aap8492

  • CrossRef
  • Google Scholar

• 41

  AjamiBBennettJLKriegerCTetzlaffWRossiFM. Local self-renewal can sustain cns microglia maintenance and function throughout adult life. Nat Neurosci (2007) 10(12):1538–43. doi: 10.1038/nn2014

  • CrossRef
  • Google Scholar

• 42

  YoungerDMuruganMRama RaoKVWuLJChandraN. Microglia receptors in animal models of traumatic brain injury. Mol Neurobiol (2019) 56(7):5202–28. doi: 10.1007/s12035-018-1428-7

  • CrossRef
  • Google Scholar

• 43

  ButlerCAPopescuASKitchenerEJAAllendorfDHPuigdellivolMBrownGC. Microglial phagocytosis of neurons in neurodegeneration, and its regulation. J Neurochem (2021) 158(3):621–39. doi: 10.1111/jnc.15327

  • CrossRef
  • Google Scholar

• 44

  BrownGCNeherJJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci (2014) 15(4):209–16. doi: 10.1038/nrn3710

  • CrossRef
  • Google Scholar

• 45

  ZhouTHuangZJSunXWZhuXWZhouLLLiMet al. Microglia polarization with M1/M2 phenotype changes in Rd1 mouse model of retinal degeneration. Front Neuroanat (2017) 11:77. doi: 10.3389/fnana.2017.00077

  • CrossRef
  • Google Scholar

• 46

  OchockaNKaminskaB. Microglia diversity in healthy and diseased brain: Insights from single-cell omics. Int J Mol Sci (2021) 22(6):3027. doi: 10.3390/ijms22063027

  • CrossRef
  • Google Scholar

• 47

  SchaferDPLehrmanEKKautzmanAGKoyamaRMardinlyARYamasakiRet al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron (2012) 74(4):691–705. doi: 10.1016/j.neuron.2012.03.026

  • CrossRef
  • Google Scholar

• 48

  WangXZhaoLZhangJFarissRNMaWKretschmerFet al. Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. J Neurosci (2016) 36(9):2827–42. doi: 10.1523/JNEUROSCI.3575-15.2016

  • CrossRef
  • Google Scholar

• 49

  RansohoffRMPerryVH. Microglial physiology: Unique stimuli, specialized responses. Annu Rev Immunol (2009) 27:119–45. doi: 10.1146/annurev.immunol.021908.132528

  • CrossRef
  • Google Scholar

• 50

  NimmerjahnAKirchhoffFHelmchenF. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science (2005) 308(5726):1314–8. doi: 10.1126/science.1110647

  • CrossRef
  • Google Scholar

• 51

  NeumannHKotterMRFranklinRJ. Debris clearance by microglia: An essential link between degeneration and regeneration. Brain (2009) 132(Pt 2):288–95. doi: 10.1093/brain/awn109

  • CrossRef
  • Google Scholar

• 52

  RohrerBPintoFRHulseKELohrHRZhangLAlmeidaJS. Multidestructive pathways triggered in photoreceptor cell death of the Rd mouse as determined through gene expression profiling. J Biol Chem (2004) 279(40):41903–10. doi: 10.1074/jbc.M405085200

  • CrossRef
  • Google Scholar

• 53

  MurakamiYIkedaYNakatakeSTachibanaTFujiwaraKYoshidaNet al. Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa. Cell Death Discovery (2015) 1:15058. doi: 10.1038/cddiscovery.2015.58

  • CrossRef
  • Google Scholar

• 54

  Vallazza-DeschampsGCiaDGongJJellaliADubocAForsterVet al. Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors. Eur J Neurosci (2005) 22(5):1013–22. doi: 10.1111/j.1460-9568.2005.04306.x

  • CrossRef
  • Google Scholar

• 55

  WrightAFChakarovaCFAbd El-AzizMMBhattacharyaSS. Photoreceptor degeneration: Genetic and mechanistic dissection of a complex trait. Nat Rev Genet (2010) 11(4):273–84. doi: 10.1038/nrg2717

  • CrossRef
  • Google Scholar

• 56

  MahalingBLowSWYBeckMKumarDAhmedSConnorTBet al. Damage-associated molecular patterns (Damps) in retinal disorders. Int J Mol Sci (2022) 23(5):2591. doi: 10.3390/ijms23052591

  • CrossRef
  • Google Scholar

• 57

  BlankTGoldmannTKochMAmannLSchonCBoninMet al. Early microglia activation precedes photoreceptor degeneration in a mouse model of Cngb1-linked retinitis pigmentosa. Front Immunol (2017) 8:1930. doi: 10.3389/fimmu.2017.01930

  • CrossRef
  • Google Scholar

• 58

  ZeissCJJohnsonEA. Proliferation of microglia, but not photoreceptors, the outer nuclear layer of the Rd-1 mouse. Invest Ophth Vis Sci (2004) 45(3):971–6. doi: 10.1167/iovs.03-0301

  • CrossRef
  • Google Scholar

• 59

  ZhangLCuiXJaureguiRParkKSJustusSTsaiYTet al. Genetic rescue reverses microglial activation in preclinical models of retinitis pigmentosa. Mol Ther (2018) 26(8):1953–64. doi: 10.1016/j.ymthe.2018.06.014

  • CrossRef
  • Google Scholar

• 60

  ReichenbachABringmannA. Glia of the human retina. Glia (2020) 68(4):768–96. doi: 10.1002/glia.23727

  • CrossRef
  • Google Scholar

• 61

  GoldmanD. Muller Glial cell reprogramming and retina regeneration. Nat Rev Neurosci (2014) 15(7):431–42. doi: 10.1038/nrn3723

  • CrossRef
  • Google Scholar

• 62

  EastlakeKBanerjeePJAngbohangACharterisDGKhawPTLimbGA. Muller Glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy. Glia (2016) 64(4):495–506. doi: 10.1002/glia.22942

  • CrossRef
  • Google Scholar

• 63

  SchmalenALorenzLGroscheAPaulyDDeegCAHauckSM. Proteomic phenotyping of stimulated Muller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity. Front Pharmacol (2021) 12:771571. doi: 10.3389/fphar.2021.771571

  • CrossRef
  • Google Scholar

• 64

  LorenzLHirmerSSchmalenAHauckSMDeegCA. Cell surface profiling of retinal Muller glial cells reveals association to immune pathways after lps stimulation. Cells (2021) 10(3):711. doi: 10.3390/cells10030711

  • CrossRef
  • Google Scholar

• 65

  SakamiSImanishiYPalczewskiK. Muller Glia phagocytose dead photoreceptor cells in a mouse model of retinal degenerative disease. FASEB J (2019) 33(3):3680–92. doi: 10.1096/fj.201801662R

  • CrossRef
  • Google Scholar

• 66

  Di PierdomenicoJMartinez-VacasAHernandez-MunozDGomez-RamirezAMValiente-SorianoFJAgudo-BarriusoMet al. Coordinated intervention of microglial and Muller cells in light-induced retinal degeneration. Invest Ophthalmol Vis Sci (2020) 61(3):47. doi: 10.1167/iovs.61.3.47

  • CrossRef
  • Google Scholar

• 67

  ArrobaAIAlvarez-LindoNvan RooijenNde la RosaEJ. Microglia-Muller glia crosstalk in the Rd10 mouse model of retinitis pigmentosa. Adv Exp Med Biol (2014) 801:373–9. doi: 10.1007/978-1-4614-3209-8_47

  • CrossRef
  • Google Scholar

• 68

  ZhangSZhangSSGongWQZhuGPWangSTWangYLet al. Muller Cell regulated microglial activation and migration in rats with n-Methyl-N-Nitrosourea-Lnduced retinal degeneration. Front Neurosci (2018) 12:890. doi: 10.3389/fnins.2018.00890

  • CrossRef
  • Google Scholar

• 69

  DevoldereJPeynshaertKDe SmedtSCRemautK. Muller Cells as a target for retinal therapy. Drug Discov Today (2019) 24(8):1483–98. doi: 10.1016/j.drudis.2019.01.023

  • CrossRef
  • Google Scholar

• 70

  ChenYXiaQZengYZhangYZhangM. Regulations of retinal inflammation: Focusing on Muller glia. Front Cell Dev Biol (2022) 10:898652. doi: 10.3389/fcell.2022.898652

  • CrossRef
  • Google Scholar

• 71

  GalanAJmaeffSBarcelonaPFBrahimiFSarunicMVSaragoviHU. In retinitis pigmentosa Trkc.T1-dependent vectorial erk activity upregulates glial tnf-alpha, causing selective neuronal death. Cell Death Dis (2017) 8(12):3222. doi: 10.1038/s41419-017-0074-8

  • CrossRef
  • Google Scholar

• 72

  Platon-CorchadoMBarcelonaPFJmaeffSMarchenaMHernandez-PintoAMHernandez-SanchezCet al. P75(Ntr) antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa. Cell Death Dis (2017) 8(7):e2922. doi: 10.1038/cddis.2017.306

  • CrossRef
  • Google Scholar

• 73

  RanaTKotlaPFullardRGorbatyukM. Tnfa knockdown in the retina promotes cone survival in a mouse model of autosomal dominant retinitis pigmentosa. Biochim Biophys Acta Mol Basis Dis (2017) 1863(1):92–102. doi: 10.1016/j.bbadis.2016.10.008

  • CrossRef
  • Google Scholar

• 74

  de la CamaraCMFOlivares-GonzalezLHervasDSalomDMillanJMRodrigoR. Infliximab reduces zaprinast-induced retinal degeneration in cultures of porcine retina. J Neuroinflamm (2014) 11:172. doi: 10.1186/s12974-014-0172-9

  • CrossRef
  • Google Scholar

• 75

  Olivares-GonzalezLVelascoSMillanJMRodrigoR. Intravitreal administration of adalimumab delays retinal degeneration in Rd10 mice. FASEB J (2020) 34(10):13839–61. doi: 10.1096/fj.202000044RR

  • CrossRef
  • Google Scholar

• 76

  Sanchez-CruzAMendezACLizasoainIde la VillaPde la RosaEJHernandez-SanchezC. Tlr2 gene deletion delays retinal degeneration in two genetically distinct mouse models of retinitis pigmentosa. Int J Mol Sci (2021) 22(15):7815. doi: 10.3390/ijms22157815

  • CrossRef
  • Google Scholar

• 77

  KohnoHChenYKevanyBMPearlmanEMiyagiMMaedaTet al. Photoreceptor proteins initiate microglial activation Via toll-like receptor 4 in retinal degeneration mediated by all-Trans-Retinal. J Biol Chem (2013) 288(21):15326–41. doi: 10.1074/jbc.M112.448712

  • CrossRef
  • Google Scholar

• 78

  Di PierdomenicoJScholzRValiente-SorianoFJSanchez-MigallonMCVidal-SanzMLangmannTet al. Neuroprotective effects of Fgf2 and minocycline in two animal models of inherited retinal degeneration. Invest Ophth Vis Sci (2018) 59(11):4392–403. doi: 10.1167/iovs.18-24621

  • CrossRef
  • Google Scholar

• 79

  HughesEHSchlichtenbredeFCMurphyCCBroderickCVan RooijenNAliRRet al. Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism. Exp Eye Res (2004) 78(6):1077–84. doi: 10.1016/j.exer.2004.02.002

  • CrossRef
  • Google Scholar

• 80

  ZhangCLeiBLamTTYangFSinhaDTsoMO. Neuroprotection of photoreceptors by minocycline in light-induced retinal degeneration. Invest Ophthalmol Vis Sci (2004) 45(8):2753–9. doi: 10.1167/iovs.03-1344

  • CrossRef
  • Google Scholar

• 81

  ScholzRSobotkaMCaramoyAStempflTMoehleCLangmannT. Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration. J Neuroinflamm (2015) 12:209. doi: 10.1186/s12974-015-0431-4

  • CrossRef
  • Google Scholar

• 82

  PengBXiaoJWangKSoKFTipoeGLLinB. Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa. J Neurosci (2014) 34(24):8139–50. doi: 10.1523/jneurosci.5200-13.2014

  • CrossRef
  • Google Scholar

• 83

  SyedaSPatelAKLeeTHackamAS. Reduced photoreceptor death and improved retinal function during retinal degeneration in mice lacking innate immunity adaptor protein Myd88. Exp Neurol (2015) 267:1–12. doi: 10.1016/j.expneurol.2015.02.027

  • CrossRef
  • Google Scholar

• 84

  GarcesKCarmyTIllianoPBrambillaRHackamAS. Increased neuroprotective microglia and photoreceptor survival in the retina from a peptide inhibitor of myeloid differentiation factor 88 (Myd88). J Mol Neurosci (2020) 70(6):968–80. doi: 10.1007/s12031-020-01503-0

  • CrossRef
  • Google Scholar

• 85

  Carmy-BennunTMyerCBhattacharyaSKHackamAS. Quantitative proteomic analysis after neuroprotective Myd88 inhibition in the retinal degeneration 10 mouse. J Cell Mol Med (2021) 25(20):9533–42. doi: 10.1111/jcmm.16893

  • CrossRef
  • Google Scholar

• 86

  AslanidisAKarlstetterMScholzRFauserSNeumannHFriedCet al. Activated Microglia/Macrophage whey acidic protein (Amwap) inhibits nfkappab signaling and induces a neuroprotective phenotype in microglia. J Neuroinflamm (2015) 12:77. doi: 10.1186/s12974-015-0296-6

  • CrossRef
  • Google Scholar

• 87

  ViringipurampeerIAMetcalfeALBasharAESivakOYanaiAMohammadiZet al. Nlrp3 inflammasome activation drives bystander cone photoreceptor cell death in a P23h rhodopsin model of retinal degeneration. Hum Mol Genet (2016) 25(8):1501–16. doi: 10.1093/hmg/ddw029

  • CrossRef
  • Google Scholar

• 88

  PuthusseryTFletcherE. Extracellular atp induces retinal photoreceptor apoptosis through activation of purinoceptors in rodents. J Comp Neurol (2009) 513(4):430–40. doi: 10.1002/cne.21964

  • CrossRef
  • Google Scholar

• 89

  ZabelMKZhaoLZhangYGonzalezSRMaWWangXet al. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by Cx3cl1-Cx3cr1 signaling in a mouse model of retinitis pigmentosa. Glia (2016) 64(9):1479–91. doi: 10.1002/glia.23016

  • CrossRef
  • Google Scholar

• 90

  WangSKXueYLRanaPHongCMCepkoCL. Soluble Cx3cl1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa. Proc Natl Acad Sci U.S.A. (2019) 116(20):10140–9. doi: 10.1073/pnas.1901787116

  • CrossRef
  • Google Scholar

• 91

  RocheSLWyse-JacksonACGomez-VicenteVLaxPRuiz-LopezAMByrneAMet al. Progesterone attenuates microglial-driven retinal degeneration and stimulates protective fractalkine-Cx3cr1 signaling. PloS One (2016) 11(11):e0165197. doi: 10.1371/journal.pone.0165197

  • CrossRef
  • Google Scholar

• 92

  RocheSLWyse-JacksonACRuiz-LopezAMByrneAMCotterTG. Fractalkine-Cx3cr1 signaling is critical for progesterone-mediated neuroprotection in the retina. Sci Rep (2017) 7:43067. doi: 10.1038/srep43067

  • CrossRef
  • Google Scholar

• 93

  KohnoHTerauchiRWatanabeSIchiharaKWatanabeTNishijimaEet al. Effect of lecithin-bound iodine treatment on inherited retinal degeneration in mice. Trans Vision Sci Technol (2021) 10(13):8. doi: 10.1167/tvst.10.13.8

  • CrossRef
  • Google Scholar

• 94

  TerauchiRKohnoHWatanabeSSaitoSWatanabeANakanoT. Minocycline decreases Ccr2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa. PloS One (2021) 16(4):e0239108. doi: 10.1371/journal.pone.0239108

  • CrossRef
  • Google Scholar

• 95

  GuoCROtaniAOishiAKojimaHMakiyamaYNakagawaSet al. Knockout of Ccr2 alleviates photoreceptor cell death in a model of retinitis pigmentosa. Exp Eye Res (2012) 104:39–47. doi: 10.1016/j.exer.2012.08.013

  • CrossRef
  • Google Scholar

• 96

  KohnoHMaedaTPerusekLPearlmanEMaedaA. Ccl3 production by microglial cells modulates disease severity in murine models of retinal degeneration. J Immunol (2014) 192(8):3816–27. doi: 10.4049/jimmunol.1301738

  • CrossRef
  • Google Scholar

• 97

  RutarMNatoliRProvisJM. Small interfering rna-mediated suppression of Ccl2 in Muller cells attenuates microglial recruitment and photoreceptor death following retinal degeneration. J Neuroinflamm (2012) 9:221. doi: 10.1186/1742-2094-9-221

  • CrossRef
  • Google Scholar

• 98

  SamardzijaMWenzelAAufenbergSThierschMReméCGrimmC. Differential role of jak-stat signaling in retinal degenerations. FASEB J (2006) 20(13):2411–3. doi: 10.1096/fj.06-5895fje

  • CrossRef
  • Google Scholar

• 99

  XieJLiYJDaiJMHeYSunDYDaiCet al. Olfactory ensheathing cells grafted into the retina of rcs rats suppress inflammation by down-regulating the Jak/Stat pathway. Front Cell Neurosci (2019) 13:341. doi: 10.3389/fncel.2019.00341

  • CrossRef
  • Google Scholar

• 100

  BrownCAgostaPMcKeeCWalkerKMazzellaMAlamriAet al. Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in Rd12 mouse model of retinitis pigmentosa. Stem Cell Res Ther (2022) 13(1):148. doi: 10.1186/s13287-022-02828-w

  • CrossRef
  • Google Scholar

• 101

  LipinskiDMBarnardARSinghMSMartinCLeeEJDaviesWILet al. Cntf gene therapy confers lifelong neuroprotection in a mouse model of human retinitis pigmentosa. Mol Ther (2015) 23(8):1308–19. doi: 10.1038/mt.2015.68

  • CrossRef
  • Google Scholar

• 102

  RheeKDNusinowitzSChaoKYuFBokDYangXJ. Cntf-mediated protection of photoreceptors requires initial activation of the cytokine receptor Gp130 in müller glial cells. Proc Natl Acad Sci U.S.A. (2013) 110(47):E4520–9. doi: 10.1073/pnas.1303604110

  • CrossRef
  • Google Scholar

• 103

  UekiYWangJChollangiSAshJD. Stat3 activation in photoreceptors by leukemia inhibitory factor is associated with protection from light damage. J Neurochem (2008) 105(3):784–96. doi: 10.1111/j.1471-4159.2007.05180.x

  • CrossRef
  • Google Scholar

• 104

  Sancho-PelluzJAlaviMVSahabogluAKustermannSFarinelliPAzadiSet al. Excessive hdac activation is critical for neurodegeneration in the Rd1 mouse. Cell Death Dis (2010) 1(2):e24. doi: 10.1038/cddis.2010.4

  • CrossRef
  • Google Scholar

• 105

  SamardzijaMCornaAGomez-SintesRJarbouiMAArmentoARogerJEet al. Hdac inhibition ameliorates cone survival in retinitis pigmentosa mice. Cell Death Differ (2021) 28(4):1317–32. doi: 10.1038/s41418-020-00653-3

  • CrossRef
  • Google Scholar

• 106

  SundaramurthiHRocheSLGriceGLMoranADillionETCampianiGet al. Selective histone deacetylase 6 inhibitors restore cone photoreceptor vision or outer segment morphology in zebrafish and mouse models of retinal blindness. Front Cell Dev Biol (2020) 8:689. doi: 10.3389/fcell.2020.00689

  • CrossRef
  • Google Scholar

• 107

  LeykJDalyCJanssen-BienholdUKennedyBNRichter-LandsbergC. Hdac6 inhibition by tubastatin a is protective against oxidative stress in a photoreceptor cell line and restores visual function in a zebrafish model of inherited blindness. Cell Death Dis (2017) 8(8):e3028. doi: 10.1038/cddis.2017.415

  • CrossRef
  • Google Scholar

• 108

  PopovaEYKawasawaYIZhangSSMBarnstableCJ. Inhibition of epigenetic modifiers Lsd1 and Hdac1 blocks rod photoreceptor death in mouse models of retinitis pigmentosa. J Neurosci (2021) 41(31):6775–92. doi: 10.1523/jneurosci.3102-20.2021

  • CrossRef
  • Google Scholar

• 109

  MittonKPGuzmanAEDeshpandeMByrdDDeLooffCMkoyanKet al. Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice. Mol Vis (2014) 20:1527–44.

  • Google Scholar

• 110

  Vent-SchmidtRYJWenRHZongZChiuCNTamBMMayCGet al. Opposing effects of valproic acid treatment mediated by histone deacetylase inhibitor activity in four transgenic X. Laevis Models Retinitis Pigmentosa J Neurosci (2017) 37(4):1039–54. doi: 10.1523/jneurosci.1647-16.2016

  • CrossRef
  • Google Scholar

• 111

  ZhaoLLiJFuYMZhangMXWangBWOuelletteJet al. Photoreceptor protection Via blockade of bet epigenetic readers in a murine model of inherited retinal degeneration. J Neuroinflamm (2017) 14(1):14. doi: 10.1186/s12974-016-0775-4

  • CrossRef
  • Google Scholar

• 112

  ZhengSJXiaoLRLiuYWangYJChengLZhangJJet al. Dznep inhibits H3k27me3 deposition and delays retinal degeneration in the Rd1 mice. Cell Death Dis (2018) 9(3):310. doi: 10.1038/s41419-018-0349-8

  • CrossRef
  • Google Scholar

• 113

  AnasagastiALara-LópezAMilla-NavarroSEscudero-ArrarásLRodríguez-HidalgoMZabaletaNet al. Inhibition of microrna 6937 delays photoreceptor and vision loss in a mouse model of retinitis pigmentosa. Pharmaceutics (2020) 12(10):913. doi: 10.3390/pharmaceutics12100913

  • CrossRef
  • Google Scholar

• 114

  KaraliMGuadagninoIMarroccoEDe CegliRCarissimoAPizzoMet al. Aav-Mir-204 protects from retinal degeneration by attenuation of microglia activation and photoreceptor cell death. Mol Ther Nucleic Acids (2020) 19:144–56. doi: 10.1016/j.omtn.2019.11.005

  • CrossRef
  • Google Scholar

• 115

  WangYHYinZYGaoLXSunDYHuXSXueLYet al. Curcumin delays retinal degeneration by regulating microglia activation in the retina of Rd1 mice. Cell Physiol Biochem (2017) 44(2):479–93. doi: 10.1159/000485085

  • CrossRef
  • Google Scholar

• 116

  VasireddyVChavaliVRMJosephVTKadamRLinJHJamisonJAet al. Rescue of photoreceptor degeneration by curcumin in transgenic rats with P23h rhodopsin mutation. PloS One (2011) 6(6):e21193. doi: 10.1371/journal.pone.0021193

  • CrossRef
  • Google Scholar

• 117

  LiuFZhangJXiangZXuDSoKFVardiNet al. Lycium barbarum polysaccharides protect retina in Rd1 mice during photoreceptor degeneration. Invest Ophthalmol Vis Sci (2018) 59(1):597–611. doi: 10.1167/iovs.17-22881

  • CrossRef
  • Google Scholar

• 118

  WangKXiaoJPengBXingFSoKFTipoeGLet al. Retinal structure and function preservation by polysaccharides of wolfberry in a mouse model of retinal degeneration. Sci Rep (2014) 4:7601. doi: 10.1038/srep07601

  • CrossRef
  • Google Scholar

• 119

  LiuFLiuXBZhouYMYuYKWangKZhouZQet al. Wolfberry-derived zeaxanthin dipalmitate delays retinal degeneration in a mouse model of retinitis pigmentosa through modulating Stat3, Ccl2 and mapk pathways. J Neurochem (2021) 158(5):1131–50. doi: 10.1111/jnc.15472

  • CrossRef
  • Google Scholar

• 120

  CorsoLCavalleroABaroniDGarbatiPPrestipinoGBistiSet al. Saffron reduces atp-induced retinal cytotoxicity by targeting P2x7 receptors. Purinergic Signal (2016) 12(1):161–74. doi: 10.1007/s11302-015-9490-3

  • CrossRef
  • Google Scholar

• 121

  Fernandez-SanchezLLaxPEsquivaGMartin-NietoJPinillaICuencaN. Safranal, a saffron constituent, attenuates retinal degeneration in P23h rats. PloS One (2012) 7(8):e43074. doi: 10.1371/journal.pone.0043074

  • CrossRef
  • Google Scholar

• 122

  WiedemannJRashidKLangmannT. Resveratrol induces dynamic changes to the microglia transcriptome, inhibiting inflammatory pathways and protecting against microglia-mediated photoreceptor apoptosis. Biochem Biophys Res Commun (2018) 501(1):239–45. doi: 10.1016/j.bbrc.2018.04.223

  • CrossRef
  • Google Scholar

• 123

  Valdes-SanchezLGarcia-DelgadoABMontero-SanchezAde la CerdaBLucasRPenalverPet al. The resveratrol prodrug Jc19 delays retinal degeneration in Rd10 mice. Retin Degener Dis: Mech Exp Ther (2019) 1185:457–62. doi: 10.1007/978-3-030-27378-1_75

  • CrossRef
  • Google Scholar

• 124

  BradleyJR. Tnf-mediated inflammatory disease. J Pathol (2008) 214(2):149–60. doi: 10.1002/path.2287

  • CrossRef
  • Google Scholar

• 125

  KallioliasGDIvashkivLB. Tnf biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol (2016) 12(1):49–62. doi: 10.1038/nrrheum.2015.169

  • CrossRef
  • Google Scholar

• 126

  SatoKLiSHGordonWCHeJBLiouGIHillJMet al. Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein. J Neurosci (2013) 33(44):17458–68. doi: 10.1523/jneurosci.1380-13.2013

  • CrossRef
  • Google Scholar

• 127

  de la CamaraCMFSequedoMDGomez-PinedoUJaijoTAllerEGarcia-TarragaPet al. Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina. Exp Eye Res (2013) 111:122–33. doi: 10.1016/j.exer.2013.03.015

  • CrossRef
  • Google Scholar

• 128

  HollingsworthTJWangXDWhiteWASimpsonRNJablonskiMM. Chronic proinflammatory signaling accelerates the rate of degeneration in a spontaneous polygenic model of inherited retinal dystrophy. Front Pharmacol (2022) 13:839424. doi: 10.3389/fphar.2022.839424

  • CrossRef
  • Google Scholar

• 129

  ZengHYZhuXAZhangCYangLPWuLMTsoMO. Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in Rd mice. Invest Ophthalmol Vis Sci (2005) 46(8):2992–9. doi: 10.1167/iovs.05-0118

  • CrossRef
  • Google Scholar

• 130

  deKozakYCotinetAGoureauOHicksDThillayeGoldenbergB. Tumor necrosis factor and nitric oxide production by resident retinal glial cells from rats presenting hereditary retinal degeneration. Ocular Immunol Inflamm (1997) 5(2):85–94. doi: 10.3109/09273949709085056

  • CrossRef
  • Google Scholar

• 131

  Lebrun-JulienFBertrandMJDe BackerOStellwagenDMoralesCRDi PoloAet al. Prongf induces tnfalpha-dependent death of retinal ganglion cells through a P75ntr non-Cell-Autonomous signaling pathway. Proc Natl Acad Sci U.S.A. (2010) 107(8):3817–22. doi: 10.1073/pnas.0909276107

  • CrossRef
  • Google Scholar

• 132

  BaiYShiZZhuoYLiuJMalakhovAKoEet al. In glaucoma the upregulated truncated Trkc.T1 receptor isoform in glia causes increased tnf-alpha production, leading to retinal ganglion cell death. Invest Ophthalmol Vis Sci (2010) 51(12):6639–51. doi: 10.1167/iovs.10-5431

  • CrossRef
  • Google Scholar

• 133

  SrinivasanBRoqueCHHempsteadBLAl-UbaidiMRRoqueRS. Microglia-derived pronerve growth factor promotes photoreceptor cell death Via P75 neurotrophin receptor. J Biol Chem (2004) 279(40):41839–45. doi: 10.1074/jbc.M402872200

  • CrossRef
  • Google Scholar

• 134

  BaiYDerghamPNedevHXuJGalanARiveraJCet al. Chronic and acute models of retinal neurodegeneration trka activity are neuroprotective whereas P75ntr activity is neurotoxic through a paracrine mechanism. J Biol Chem (2010) 285(50):39392–400. doi: 10.1074/jbc.M110.147801

  • CrossRef
  • Google Scholar

• 135

  JangDILeeAHShinHYSongHRParkJHKangTBet al. The role of tumor necrosis factor alpha (Tnf-alpha) in autoimmune disease and current tnf-alpha inhibitors in therapeutics. Int J Mol Sci (2021) 22(5):2719. doi: 10.3390/ijms22052719

  • CrossRef
  • Google Scholar

• 136

  KuhnKDEdamuraKBhatiaNChengIClarkSAHaynesCVet al. Molecular dissection of tnfr-tnf alpha bidirectional signaling reveals both cooperative and antagonistic interactions with P75 neurotrophic factor receptor in axon patterning. Mol Cell Neurosci (2020) 103:103467. doi: 10.1016/j.mcn.2020.103467

  • CrossRef
  • Google Scholar

• 137

  MuliyilSLevetCDusterhoftSDullooICowleySAFreemanM. Adam17-triggered tnf signalling protects the ageing drosophila retina from lipid droplet-mediated degeneration. EMBO J (2020) 39(17):e104415. doi: 10.15252/embj.2020104415

  • CrossRef
  • Google Scholar

• 138

  BenootTPiccioniEDe RidderKGoyvaertsC. Tnfα and immune checkpoint inhibition: Friend or foe for lung cancer? Int J Mol Sci (2021) 22(16):8691. doi: 10.3390/ijms22168691

  • CrossRef
  • Google Scholar

• 139

  TanzerMCBludauIStaffordCAHornungVMannM. Phosphoproteome profiling uncovers a key role for cdks in tnf signaling. Nat Commun (2021) 12(1):6053. doi: 10.1038/s41467-021-26289-6

  • CrossRef
  • Google Scholar

• 140

  DichtlSSaninDEKossCKWillenborgSPetzoldATanzerMCet al. Gene-selective transcription promotes the inhibition of tissue reparative macrophages by tnf. Life Sci Alliance (2022) 5(4):e202101315. doi: 10.26508/lsa.202101315

  • CrossRef
  • Google Scholar

• 141

  TanzerMC. A proteomic perspective on tnf-mediated signalling and cell death. Biochem Soc Trans (2022) 50(1):13–20. doi: 10.1042/BST20211114

  • CrossRef
  • Google Scholar

• 142

  WangMMaWZhaoLFarissRNWongWT. Adaptive müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina. J Neuroinflamm (2011) 8:173. doi: 10.1186/1742-2094-8-173

  • CrossRef
  • Google Scholar

• 143

  AgcaCGublerATraberGBeckCImsandCAilDet al. P38 mapk signaling acts upstream of lif-dependent neuroprotection during photoreceptor degeneration. Cell Death Dis (2013) 4(9):e785. doi: 10.1038/cddis.2013.323

  • CrossRef
  • Google Scholar

• 144

  Coelho-SantosVGoncalvesJFontes-RibeiroCSilvaAP. Prevention of methamphetamine-induced microglial cell death by tnf-alpha and il-6 through activation of the jak-stat pathway. J Neuroinflamm (2012) 9:103. doi: 10.1186/1742-2094-9-103

  • CrossRef
  • Google Scholar

• 145

  HuXXuMXZhouHChengSLiFMiaoYet al. Tumor necrosis factor-alpha aggravates gliosis and inflammation of activated retinal müller cells. Biochem Biophys Res Commun (2020) 531(3):383–9. doi: 10.1016/j.bbrc.2020.07.102

  • CrossRef
  • Google Scholar

• 146

  FedericoSPozzettiLPapaACarulloGGemmaSButiniSet al. Modulation of the innate immune response by targeting toll-like receptors: A perspective on their agonists and antagonists. J Med Chem (2020) 63(22):13466–513. doi: 10.1021/acs.jmedchem.0c01049

  • CrossRef
  • Google Scholar

• 147

  FukataMVamadevanASAbreuMT. Toll-like receptors (Tlrs) and nod-like receptors (Nlrs) in inflammatory disorders. Semin Immunol (2009) 21(4):242–53. doi: 10.1016/j.smim.2009.06.005

  • CrossRef
  • Google Scholar

• 148

  AkiraSUematsuSTakeuchiO. Pathogen recognition and innate immunity. Cell (2006) 124(4):783–801. doi: 10.1016/j.cell.2006.02.015

  • CrossRef
  • Google Scholar

• 149

  JiangLXuFHeWJChenLFZhongHBWuYet al. Cd200fc reduces Tlr4-mediated inflammatory responses in lps-induced rat primary microglial cells Via inhibition of the nf-kappa b pathway. Inflamm Res (2016) 65(7):521–32. doi: 10.1007/s00011-016-0932-3

  • CrossRef
  • Google Scholar

• 150

  GorinaRFont-NievesMMarquez-KisinouskyLSantaluciaTPlanasAM. Astrocyte Tlr4 activation induces a proinflammatory environment through the interplay between Myd88-dependent nfkappab signaling, mapk, and Jak1/Stat1 pathways. Glia (2011) 59(2):242–55. doi: 10.1002/glia.21094

  • CrossRef
  • Google Scholar

• 151

  SwaroopSSenguptaNSuryawanshiARAdlakhaYKBasuA. Hsp60 plays a regulatory role in il-1beta-Induced microglial inflammation Via Tlr4-P38 mapk axis. J Neuroinflamm (2016) 13:27. doi: 10.1186/s12974-016-0486-x

  • CrossRef
  • Google Scholar

• 152

  HuangZZhouTSunXZhengYChengBLiMet al. Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through Tlr4 activation. Cell Death Differ (2018) 25(1):180–9. doi: 10.1038/cdd.2017.141

  • CrossRef
  • Google Scholar

• 153

  KoMKSaraswathySParikhJGRaoNA. The role of Tlr4 activation in photoreceptor mitochondrial oxidative stress. Invest Ophth Vis Sci (2011) 52(8):5824–35. doi: 10.1167/iovs.10-6357

  • CrossRef
  • Google Scholar

• 154

  JackCSArbourNManusowJMontgrainVBlainMMcCreaEet al. Tlr signaling tailors innate immune responses in human microglia and astrocytes. J Immunol (2005) 175(7):4320–30. doi: 10.4049/jimmunol.175.7.4320

  • CrossRef
  • Google Scholar

• 155

  ChinneryHRNaranjo GolborneCLeongCMChenWForresterJVMcMenaminPG. Retinal microglial activation following topical application of intracellular toll-like receptor ligands. Invest Ophthalmol Vis Sci (2015) 56(12):7377–86. doi: 10.1167/iovs.15-17587

  • CrossRef
  • Google Scholar

• 156

  PisetskyDSGauleyJUllalAJ. Hmgb1 and microparticles as mediators of the immune response to cell death. Antioxid Redox Signal (2011) 15(8):2209–19. doi: 10.1089/ars.2010.3865

  • CrossRef
  • Google Scholar

• 157

  DasNDewanVGracePMGunnRJTamuraRTzarumNet al. Hmgb1 activates proinflammatory signaling Via Tlr5 leading to allodynia. Cell Rep (2016) 17(4):1128–40. doi: 10.1016/j.celrep.2016.09.076

  • CrossRef
  • Google Scholar

• 158

  LinFShanWZhengYPanLZuoZ. Toll-like receptor 2 activation and up-regulation by high mobility group box-1 contribute to post-operative neuroinflammation and cognitive dysfunction in mice. J Neurochem (2021) 158(2):328–41. doi: 10.1111/jnc.15368

  • CrossRef
  • Google Scholar

• 159

  ZhuSHLiuBQHaoMJFanYXQianCTengPet al. Paeoniflorin suppressed high glucose-induced retinal microglia mmp-9 expression and inflammatory response Via inhibition of Tlr4/Nf-kappab pathway through upregulation of Socs3 in diabetic retinopathy. Inflammation (2017) 40(5):1475–86. doi: 10.1007/s10753-017-0571-z

  • CrossRef
  • Google Scholar

• 160

  BohmMRSchallenbergMBrockhausKMelkonyanHThanosS. The pro-inflammatory role of high-mobility group box 1 protein (Hmgb-1) in photoreceptors and retinal explants exposed to elevated pressure. Lab Invest (2016) 96(4):409–27. doi: 10.1038/labinvest.2015.156

  • CrossRef
  • Google Scholar

• 161

  SakamotoKMizutaAFujimuraKKurauchiYMoriANakaharaTet al. High-mobility group box-1 is involved in nmda-induced retinal injury the in rat retina. Exp Eye Res (2015) 137:63–70. doi: 10.1016/j.exer.2015.06.003

  • CrossRef
  • Google Scholar

• 162

  LiuLJiangYSteinleJJ. Glycyrrhizin protects the diabetic retina against permeability, neuronal, and vascular damage through anti-inflammatory mechanisms. J Clin Med (2019) 8(7):957. doi: 10.3390/jcm8070957

  • CrossRef
  • Google Scholar

• 163

  TonnerHHunnSAulerNSchmelterCBeutgenVMvon PeinHDet al. A monoclonal anti-Hmgb1 antibody attenuates neurodegeneration in an experimental animal model of glaucoma. Int J Mol Sci (2022) 23(8):4107. doi: 10.3390/ijms23084107

  • CrossRef
  • Google Scholar

• 164

  NikodemovaMDuncanIDWattersJJ. Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and ikappabalpha degradation in a stimulus-specific manner in microglia. J Neurochem (2006) 96(2):314–23. doi: 10.1111/j.1471-4159.2005.03520.x

  • CrossRef
  • Google Scholar

• 165

  HenryCJHuangYWynneAHankeMHimlerJBaileyMTet al. Minocycline attenuates lipopolysaccharide (Lps)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflamm (2008) 5:15. doi: 10.1186/1742-2094-5-15

  • CrossRef
  • Google Scholar

• 166

  HuFKuMCMarkovicDDzayeOLehnardtSSynowitzMet al. Glioma-associated microglial Mmp9 expression is upregulated by Tlr2 signaling and sensitive to minocycline. Int J Cancer (2014) 135(11):2569–78. doi: 10.1002/ijc.28908

  • CrossRef
  • Google Scholar

• 167

  HalderSKMatsunagaHIshiiKJAkiraSMiyakeKUedaH. Retinal cell type-specific prevention of ischemia-induced damages by lps-Tlr4 signaling through microglia. J Neurochem (2013) 126(2):243–60. doi: 10.1111/jnc.12262

  • CrossRef
  • Google Scholar

• 168

  KuCAChiodoVABoyeSLHayesAGoldbergAFXHauswirthWWet al. Viral-mediated vision rescue of a novel Aipl1 cone-rod dystrophy model. Hum Mol Genet (2015) 24(3):670–84. doi: 10.1093/hmg/ddu487

  • CrossRef
  • Google Scholar

• 169

  ChenLZhengLChenPLiangG. Myeloid differentiation primary response protein 88 (Myd88): The central hub of Tlr/Il-1r signaling. J Med Chem (2020) 63(22):13316–29. doi: 10.1021/acs.jmedchem.0c00884

  • CrossRef
  • Google Scholar

• 170

  KawaiTAdachiOOgawaTTakedaKAkiraS. Unresponsiveness of Myd88-deficient mice to endotoxin. Immunity (1999) 11(1):115–22. doi: 10.1016/s1074-7613(00)80086-2

  • CrossRef
  • Google Scholar

• 171

  GuoHCallawayJBTingJP. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat Med (2015) 21(7):677–87. doi: 10.1038/nm.3893

  • CrossRef
  • Google Scholar

• 172

  WeberAWasiliewPKrachtM. Interleukin-1beta (Il-1beta) processing pathway. Sci Signal (2010) 3(105):cm2. doi: 10.1126/scisignal.3105cm2

  • CrossRef
  • Google Scholar

• 173

  SwansonKVDengMTingJP. The Nlrp3 inflammasome: Molecular activation and regulation to therapeutics. Nat Rev Immunol (2019) 19(8):477–89. doi: 10.1038/s41577-019-0165-0

  • CrossRef
  • Google Scholar

• 174

  ZhangYXuYSunQXueSGuanHJiM. Activation of P2x7r- Nlrp3 pathway in retinal microglia contribute to retinal ganglion cells death in chronic ocular hypertension (Coh). Exp Eye Res (2019) 188:107771. doi: 10.1016/j.exer.2019.107771

  • CrossRef
  • Google Scholar

• 175

  FletcherEL. Advances in understanding the mechanisms of retinal degenerations. Clin Exp Optom (2020) 103(6):723–32. doi: 10.1111/cxo.13146

  • CrossRef
  • Google Scholar

• 176

  VesseyKAGreferathUAplinFPJoblingAIPhippsJAHoTet al. Adenosine triphosphate-induced photoreceptor death and retinal remodeling in rats. J Comp Neurol (2014) 522(13):2928–50. doi: 10.1002/cne.23558

  • CrossRef
  • Google Scholar

• 177

  NotomiSHisatomiTKanemaruTTakedaAIkedaYEnaidaHet al. Critical involvement of extracellular atp acting on P2rx7 purinergic receptors in photoreceptor cell death. Am J Pathol (2011) 179(6):2798–809. doi: 10.1016/j.ajpath.2011.08.035

  • CrossRef
  • Google Scholar

• 178

  CampagnoKEMitchellCH. The P2x7 receptor in microglial cells modulates the endolysosomal axis, autophagy, and phagocytosis. Front Cell Neurosci (2021) 15:645244. doi: 10.3389/fncel.2021.645244

  • CrossRef
  • Google Scholar

• 179

  BasuAKradyJKLevisonSW. Interleukin-1: A master regulator of neuroinflammation. J Neurosci Res (2004) 78(2):151–6. doi: 10.1002/jnr.20266

  • CrossRef
  • Google Scholar

• 180

  GabayCLamacchiaCPalmerG. Il-1 pathways in inflammation and human diseases. Nat Rev Rheumatol (2010) 6(4):232–41. doi: 10.1038/nrrheum.2010.4

  • CrossRef
  • Google Scholar

• 181

  BamforthSDLightmanSLGreenwoodJ. Ultrastructural analysis of interleukin-1 beta-induced leukocyte recruitment to the rat retina. Invest Ophthalmol Vis Sci (1997) 38(1):25–35.

  • Google Scholar

• 182

  Charles-MessanceHBlotGCouturierAVignaudLTouhamiSBeguierFet al. Il-1beta induces rod degeneration through the disruption of retinal glutamate homeostasis. J Neuroinflamm (2020) 17(1):1. doi: 10.1186/s12974-019-1655-5

  • CrossRef
  • Google Scholar

• 183

  DinarelloCA. Overview of the il-1 family in innate inflammation and acquired immunity. Immunol Rev (2018) 281(1):8–27. doi: 10.1111/imr.12621

  • CrossRef
  • Google Scholar

• 184

  ToddLPalazzoISuarezLLiuXVolkovLHoangTVet al. Reactive microglia and Il1beta/Il-1r1-Signaling mediate neuroprotection in excitotoxin-damaged mouse retina. J Neuroinflamm (2019) 16(1):118. doi: 10.1186/s12974-019-1505-5

  • CrossRef
  • Google Scholar

• 185

  WolfYYonaSKimKWJungS. Microglia, seen from the Cx3cr1 angle. Front Cell Neurosci (2013) 7:26. doi: 10.3389/fncel.2013.00026

  • CrossRef
  • Google Scholar

• 186

  LuoPChuSFZhangZXiaCYChenNH. Fractalkine/Cx3cr1 is involved in the cross-talk between neuron and glia in neurological diseases. Brain Res Bull (2019) 146:12–21. doi: 10.1016/j.brainresbull.2018.11.017

  • CrossRef
  • Google Scholar

• 187

  SheridanGKMurphyKJ. Neuron-glia crosstalk in health and disease: Fractalkine and Cx3cr1 take centre stage. Open Biol (2013) 3(12):130181. doi: 10.1098/rsob.130181

  • CrossRef
  • Google Scholar

• 188

  LiangKJLeeJEWangYDMaWFontainhasAMFarissRNet al. Regulation of dynamic behavior of retinal microglia by Cx3cr1 signaling. Invest Ophthalmol Vis Sci (2009) 50(9):4444–51. doi: 10.1167/iovs.08-3357

  • CrossRef
  • Google Scholar

• 189

  JoblingAIWaughMVesseyKAPhippsJATrogrlicLGreferathUet al. The role of the microglial Cx3cr1 pathway in the postnatal maturation of retinal photoreceptors. J Neurosci (2018) 38(20):4708–23. doi: 10.1523/JNEUROSCI.2368-17.2018

  • CrossRef
  • Google Scholar

• 190

  YouMLongCWanYGuoHShenJLiMet al. Neuron derived fractalkine promotes microglia to absorb hematoma Via Cd163/Ho-1 after intracerebral hemorrhage. Cell Mol Life Sci (2022) 79(5):224. doi: 10.1007/s00018-022-04212-6

  • CrossRef
  • Google Scholar

• 191

  PuntambekarSSMoutinhoMLinPBJadhavVTumbleson-BrinkDBalajiAet al. Cx3cr1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in alzheimer's disease. Mol Neurodegener (2022) 17(1):47. doi: 10.1186/s13024-022-00545-9

  • CrossRef
  • Google Scholar

• 192

  CardonaAEPioroEPSasseMEKostenkoVCardonaSMDijkstraIMet al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci (2006) 9(7):917–24. doi: 10.1038/nn1715

  • CrossRef
  • Google Scholar

• 193

  HuSJCalippeBLavaletteSRoubeixCMontassarFHoussetMet al. Upregulation of P2rx7 in Cx3cr1-deficient mononuclear phagocytes leads to increased interleukin-1beta secretion and photoreceptor neurodegeneration. J Neurosci (2015) 35(18):6987–96. doi: 10.1523/JNEUROSCI.3955-14.2015

  • CrossRef
  • Google Scholar

• 194

  MuraiNMitalipovaMJaenischR. Functional analysis of Cx3cr1 in human induced pluripotent stem (Ips) cell-derived microglia-like cells. Eur J Neurosci (2020) 52(7):3667–78. doi: 10.1111/ejn.14879

  • CrossRef
  • Google Scholar

• 195

  GyonevaSHosurRGosselinDZhangBOuyangZCotleurACet al. Cx3cr1-deficient microglia exhibit a premature aging transcriptome. Life Sci Alliance (2019) 2(6):e201900453. doi: 10.26508/lsa.201900453

  • CrossRef
  • Google Scholar

• 196

  ZiegerMAhneltPKUhrinP. Cx3cl1 (Fractalkine) protein expression in normal and degenerating mouse retina: In vivo studies. PloS One (2014) 9(9):e106562. doi: 10.1371/journal.pone.0106562

  • CrossRef
  • Google Scholar

• 197

  JiangMXieHZhangCWangTTianHLuLet al. Enhancing Fractalkine/Cx3cr1 signalling pathway can reduce neuroinflammation by attenuating microglia activation in experimental diabetic retinopathy. J Cell Mol Med (2022) 26(4):1229–44. doi: 10.1111/jcmm.17179

  • CrossRef
  • Google Scholar

• 198

  KarlenSJMillerEBWangXLLevineESZawadzkiRJBurnsME. Monocyte infiltration rather than microglia proliferation dominates the early immune response to rapid photoreceptor degeneration. J Neuroinflamm (2018) 15(1):344. doi: 10.1186/s12974-018-1365-4

  • CrossRef
  • Google Scholar

• 199

  FengCWangXLiuTZhangMXuGNiY. Expression of Ccl2 and its receptor in activation and migration of microglia and monocytes induced by photoreceptor apoptosis. Mol Vis (2017) 23:765–77.

  • Google Scholar

• 200

  KuzielWAMorganSJDawsonTCGriffinSSmithiesOLeyKet al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in cc chemokine receptor 2. Proc Natl Acad Sci U.S.A. (1997) 94(22):12053–8. doi: 10.1073/pnas.94.22.12053

  • CrossRef
  • Google Scholar

• 201

  SennlaubFAuvynetCCalippeBLavaletteSPoupelLHuSJet al. Ccr2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. EMBO Mol Med (2013) 5(11):1775–93. doi: 10.1002/emmm.201302692

  • CrossRef
  • Google Scholar

• 202

  FukudaSNaganoMYamashitaTKimuraKTsuboiISalazarGet al. Functional endothelial progenitor cells selectively recruit neurovascular protective monocyte-derived F4/80(+)/Ly6c(+) macrophages in a mouse model of retinal degeneration. Stem Cells (2013) 31(10):2149–61. doi: 10.1002/stem.1469

  • CrossRef
  • Google Scholar

• 203

  XinPXuXDengCLiuSWangYZhouXet al. The role of Jak/Stat signaling pathway and its inhibitors in diseases. Int Immunopharmacol (2020) 80:106210. doi: 10.1016/j.intimp.2020.106210

  • CrossRef
  • Google Scholar

• 204

  DarnellJEJr.KerrIMStarkGR. Jak-stat pathways and transcriptional activation in response to ifns and other extracellular signaling proteins. Science (1994) 264(5164):1415–21. doi: 10.1126/science.8197455

  • CrossRef
  • Google Scholar

• 205

  LuoYAlexanderMGadinaMO'SheaJJMeylanFSchwartzDM. Jak-stat signaling in human disease: From genetic syndromes to clinical inhibition. J Allergy Clin Immunol (2021) 148(4):911–25. doi: 10.1016/j.jaci.2021.08.004

  • CrossRef
  • Google Scholar

• 206

  ZhangSSWeiJYLiCBarnstableCJFuXY. Expression and activation of stat proteins during mouse retina development. Exp Eye Res (2003) 76(4):421–31. doi: 10.1016/s0014-4835(03)00002-2

  • CrossRef
  • Google Scholar

• 207

  YuCRMahdiRMLiuXBZhangANakaTKishimotoTet al. Socs1 regulates Ccr7 expression and migration of Cd4(+) T cells into peripheral tissues. J Immunol (2008) 181(2):1190–8. doi: 10.4049/jimmunol.181.2.1190

  • CrossRef
  • Google Scholar

• 208

  LyAMerl-PhamJPrillerMGruhnFSenningerNUeffingMet al. Proteomic profiling suggests central role of stat signaling during retinal degeneration in the Rd10 mouse model. J Proteome Res (2016) 15(4):1350–9. doi: 10.1021/acs.jproteome.6b00111

  • CrossRef
  • Google Scholar

• 209

  LangeCThierschMSamardzijaMGrimmC. The differential role of Jak/Stat signaling in retinal degeneration. Adv Exp Med Biol (2010) 664:601–7. doi: 10.1007/978-1-4419-1399-9_69

  • CrossRef
  • Google Scholar

• 210

  ChenSDongZChengMZhaoYWangMSaiNet al. Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized Stat3 overactivation following ischemic stroke. J Neuroinflamm (2017) 14(1):187. doi: 10.1186/s12974-017-0963-x

  • CrossRef
  • Google Scholar

• 211

  FanZZhangWCaoQZouLFanXQiCet al. Jak2/Stat3 pathway regulates microglia polarization involved in hippocampal inflammatory damage due to acute paraquat exposure. Ecotoxicol Environ Saf (2022) 234:113372. doi: 10.1016/j.ecoenv.2022.113372

  • CrossRef
  • Google Scholar

• 212

  KorovinaINeuwirthASprottDTroullinakiMPoitzDMDeussenAet al. Myeloid Socs3 deficiency regulates angiogenesis Via enhanced apoptotic endothelial cell engulfment. J Innate Immun (2020) 12(3):248–56. doi: 10.1159/000502645

  • CrossRef
  • Google Scholar

• 213

  ZhangXHeBLiHWangYZhouYWangWet al. Socs3 attenuates gm-Csf/Ifn-Γ-Mediated inflammation during spontaneous spinal cord regeneration. Neurosci Bull (2020) 36(7):778–92. doi: 10.1007/s12264-020-00493-8

  • CrossRef
  • Google Scholar

• 214

  HeCYuCRMattapallilMJSunLLarkinJEgwuaguCE. Socs1 mimetic peptide suppresses chronic intraocular inflammatory disease (Uveitis). Mediators Inflammation (2016) 2016:2939370. doi: 10.1155/2016/2939370

  • CrossRef
  • Google Scholar

• 215

  BirchDGBennettLDDuncanJLWeleberRGPennesiME. Long-term follow-up of patients with retinitis pigmentosa receiving intraocular ciliary neurotrophic factor implants. Am J Ophthalmol (2016) 170:10–4. doi: 10.1016/j.ajo.2016.07.013

  • CrossRef
  • Google Scholar

• 216

  BirchDGWeleberRGDuncanJLJaffeGJTaoW. Ciliary neurotrophic factor retinitis pigmentosa study g. randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. Am J Ophthalmol (2013) 156(2):283–92.e1. doi: 10.1016/j.ajo.2013.03.021

  • CrossRef
  • Google Scholar

• 217

  KirschMTrautmannNErnstMHofmannHD. Involvement of Gp130-associated cytokine signaling in müller cell activation following optic nerve lesion. Glia (2010) 58(7):768–79. doi: 10.1002/glia.20961

  • CrossRef
  • Google Scholar

• 218

  JolySLangeCThierschMSamardzijaMGrimmC. Leukemia inhibitory factor extends the lifespan of injured photoreceptors in vivo. J Neurosci (2008) 28(51):13765–74. doi: 10.1523/JNEUROSCI.5114-08.2008

  • CrossRef
  • Google Scholar

• 219

  RattnerANathansJ. The genomic response to retinal disease and injury: Evidence for endothelin signaling from photoreceptors to glia. J Neurosci (2005) 25(18):4540–9. doi: 10.1523/JNEUROSCI.0492-05.2005

  • CrossRef
  • Google Scholar

• 220

  AgcaCBoldtKGublerAMeneauICorpetASamardzijaMet al. Expression of leukemia inhibitory factor in müller glia cells is regulated by a redox-dependent mrna stability mechanism. BMC Biol (2015) 13:30. doi: 10.1186/s12915-015-0137-1

  • CrossRef
  • Google Scholar

• 221

  BurgiSSamardzijaMGrimmC. Endogenous leukemia inhibitory factor protects photoreceptor cells against light-induced degeneration. Mol Vis (2009) 15:1631–7.

  • Google Scholar

• 222

  CooreyNJShenWZhuLGilliesMC. Differential expression of il-6/Gp130 cytokines, jak-stat signaling and neuroprotection after müller cell ablation in a transgenic mouse model. Invest Ophthalmol Vis Sci (2015) 56(4):2151–61. doi: 10.1167/iovs.14-15695

  • CrossRef
  • Google Scholar

• 223

  UekiYChollangiSLeYZAshJD. Gp130 activation in müller cells is not essential for photoreceptor protection from light damage. Adv Exp Med Biol (2010) 664:655–61. doi: 10.1007/978-1-4419-1399-9_75

  • CrossRef
  • Google Scholar

• 224

  UekiYLeYZChollangiSMullerWAshJD. Preconditioning-induced protection of photoreceptors requires activation of the signal-transducing receptor Gp130 in photoreceptors. Proc Natl Acad Sci U.S.A. (2009) 106(50):21389–94. doi: 10.1073/pnas.0906156106

  • CrossRef
  • Google Scholar

• 225

  SkvortsovaKIovinoNBogdanovicO. Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol (2018) 19(12):774–90. doi: 10.1038/s41580-018-0074-2

  • CrossRef
  • Google Scholar

• 226

  HaberlandMMontgomeryRLOlsonEN. The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat Rev Genet (2009) 10(1):32–42. doi: 10.1038/nrg2485

  • CrossRef
  • Google Scholar

• 227

  PortelaAEstellerM. Epigenetic modifications and human disease. Nat Biotechnol (2010) 28(10):1057–68. doi: 10.1038/nbt.1685

  • CrossRef
  • Google Scholar

• 228

  ZhangLLuQChangC. Epigenetics in health and disease. Adv Exp Med Biol (2020) 1253:3–55. doi: 10.1007/978-981-15-3449-2_1

  • CrossRef
  • Google Scholar

• 229

  Alaskhar AlhamweBKhalailaRWolfJvon BulowVHarbHAlhamdanFet al. Histone modifications and their role in epigenetics of atopy and allergic diseases. Allergy Asthma Clin Immunol (2018) 14:39. doi: 10.1186/s13223-018-0259-4

  • CrossRef
  • Google Scholar

• 230

  TrifunovicDPetridouEComitatoAMarigoVUeffingMPaquet-DurandF. Primary rod and cone degeneration is prevented by hdac inhibition. Retin Degener Dis: Mech Exp Ther (2018) 1074:367–73. doi: 10.1007/978-3-319-75402-4_45

  • CrossRef
  • Google Scholar

• 231

  KannanVBrouwerNHanischUKRegenTEggenBJBoddekeHW. Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J Neurosci Res (2013) 91(9):1133–42. doi: 10.1002/jnr.23221

  • CrossRef
  • Google Scholar

• 232

  PatnalaRArumugamTVGuptaNDheenST. Hdac inhibitor sodium butyrate-mediated epigenetic regulation enhances neuroprotective function of microglia during ischemic stroke. Mol Neurobiol (2017) 54(8):6391–411. doi: 10.1007/s12035-016-0149-z

  • CrossRef
  • Google Scholar

• 233

  DurhamBSGriggRWoodIC. Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism. J Neurochem (2017) 143(2):214–24. doi: 10.1111/jnc.14144

  • CrossRef
  • Google Scholar

• 234

  YangHNiWWeiPLiSGaoXSuJet al. Hdac inhibition reduces white matter injury after intracerebral hemorrhage. J Cereb Blood Flow Metab (2021) 41(5):958–74. doi: 10.1177/0271678X20942613

  • CrossRef
  • Google Scholar

• 235

  ChenSYeJChenXShiJWuWLinWet al. Valproic acid attenuates traumatic spinal cord injury-induced inflammation Via Stat1 and nf-kappab pathway dependent of Hdac3. J Neuroinflamm (2018) 15(1):150. doi: 10.1186/s12974-018-1193-6

  • CrossRef
  • Google Scholar

• 236

  IwagawaTWatanabeS. Molecular mechanisms of H3k27me3 and H3k4me3 in retinal development. Neurosci Res (2019) 138:43–8. doi: 10.1016/j.neures.2018.09.010

  • CrossRef
  • Google Scholar

• 237

  MbefoMBergerASchouweyKGerardXKosticCBeryozkinAet al. Enhancer of zeste homolog 2 (Ezh2) contributes to rod photoreceptor death process in several forms of retinal degeneration and its activity can serve as a biomarker for therapy efficacy. Int J Mol Sci (2021) 22(17):9331. doi: 10.3390/ijms22179331

  • CrossRef
  • Google Scholar

• 238

  ZhangXWangYYuanJLiNPeiSXuJet al. Macrophage/Microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. J Exp Med (2018) 215(5):1365–82. doi: 10.1084/jem.20171417

  • CrossRef
  • Google Scholar

• 239

  YuanJZhuQZhangXWenZZhangGLiNet al. Ezh2 competes with P53 to license lncrna Neat1 transcription for inflammasome activation. Cell Death Differ (2022) 29(10):2009–23. doi: 10.1038/s41418-022-00992-3

  • CrossRef
  • Google Scholar

• 240

  ChenLHeikkinenLWangCYangYSunHWongG. Trends in the development of mirna bioinformatics tools. Brief Bioinform (2019) 20(5):1836–52. doi: 10.1093/bib/bby054

  • CrossRef
  • Google Scholar

• 241

  RehTAHindgesR. Micrornas in retinal development. Annu Rev Vis Sci (2018) 4:25–44. doi: 10.1146/annurev-vision-091517-034357

  • CrossRef
  • Google Scholar

• 242

  XiangLChenXJWuKCZhangCJZhouGHLvJNet al. Mir-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance. Proc Natl Acad Sci U.S.A. (2017) 114(24):6376–81. doi: 10.1073/pnas.1618757114

  • CrossRef
  • Google Scholar

• 243

  AnasagastiAEzquerra-InchaustiMBarandikaOMuñoz-CullaMCaffarelMMOtaeguiDet al. Expression profiling analysis reveals key microrna-mrna interactions in early retinal degeneration in retinitis pigmentosa. Invest Ophthalmol Vis Sci (2018) 59(6):2381–92. doi: 10.1167/iovs.18-24091

  • CrossRef
  • Google Scholar

• 244

  GeniniSGuziewiczKEBeltranWAAguirreGD. Altered mirna expression in canine retinas during normal development and in models of retinal degeneration. BMC Genomics (2014) 15:172. doi: 10.1186/1471-2164-15-172

  • CrossRef
  • Google Scholar

• 245

  ChenYLinJSchlottererAKurowskiLHoffmannSHammadSet al. Microrna-124 alleviates retinal vasoregression Via regulating microglial polarization. Int J Mol Sci (2021) 22(20):11068. doi: 10.3390/ijms222011068

  • CrossRef
  • Google Scholar

• 246

  BurgalettoCPlataniaCBMDi BenedettoGMunafoAGiurdanellaGFedericoCet al. Targeting the mirna-155/Tnfsf10 network restrains inflammatory response in the retina in a mouse model of alzheimer's disease. Cell Death Dis (2021) 12(10):905. doi: 10.1038/s41419-021-04165-x

  • CrossRef
  • Google Scholar

• 247

  FernandoNWongJHCDasSDietrichCAggio-BruceRCioancaAVet al. Microrna-223 regulates retinal function and inflammation in the healthy and degenerating retina. Front Cell Dev Biol (2020) 8:516. doi: 10.3389/fcell.2020.00516

  • CrossRef
  • Google Scholar

• 248

  CiccaroneFTagliatestaSCaiafaPZampieriM. DNA Methylation dynamics in aging: How far are we from understanding the mechanisms? Mech Ageing Dev (2018) 174:3–17. doi: 10.1016/j.mad.2017.12.002

  • CrossRef
  • Google Scholar

• 249

  RheeKDYuJZhaoCYFanGYangXJ. Dnmt1-dependent DNA methylation is essential for photoreceptor terminal differentiation and retinal neuron survival. Cell Death Dis (2012) 3:e427. doi: 10.1038/cddis.2012.165

  • CrossRef
  • Google Scholar

• 250

  FarinelliPPereraAArango-GonzalezBTrifunovicDWagnerMCarellTet al. DNA Methylation and differential gene regulation in photoreceptor cell death. Cell Death Dis (2014) 5(12):e1558. doi: 10.1038/cddis.2014.512

  • CrossRef
  • Google Scholar

• 251

  DvoriantchikovaGLypkaKRIvanovD. The potential role of epigenetic mechanisms in the development of retinitis pigmentosa and related photoreceptor dystrophies. Front Genet (2022) 13:827274. doi: 10.3389/fgene.2022.827274

  • CrossRef
  • Google Scholar

• 252

  NeteaMGJoostenLALatzEMillsKHNatoliGStunnenbergHGet al. Trained immunity: A program of innate immune memory in health and disease. Science (2016) 352(6284):aaf1098. doi: 10.1126/science.aaf1098

  • CrossRef
  • Google Scholar

• 253

  NeteaMGDominguez-AndresJBarreiroLBChavakisTDivangahiMFuchsEet al. Defining trained immunity and its role in health and disease. Nat Rev Immunol (2020) 20(6):375–88. doi: 10.1038/s41577-020-0285-6

  • CrossRef
  • Google Scholar

• 254

  RodriguezRMSuarez-AlvarezBLopez-LarreaC. Therapeutic epigenetic reprogramming of trained immunity in myeloid cells. Trends Immunol (2019) 40(1):66–80. doi: 10.1016/j.it.2018.11.006

  • CrossRef
  • Google Scholar

• 255

  NeherJJCunninghamC. Priming microglia for innate immune memory in the brain. Trends Immunol (2019) 40(4):358–74. doi: 10.1016/j.it.2019.02.001

  • CrossRef
  • Google Scholar

• 256

  WendelnACDegenhardtKKauraniLGertigMUlasTJainGet al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature (2018) 556(7701):332–8. doi: 10.1038/s41586-018-0023-4

  • CrossRef
  • Google Scholar

• 257

  NoaillesAManeuVCampelloLLaxPCuencaN. Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy. Cell Death Dis (2018) 9(3):350. doi: 10.1038/s41419-018-0355-x

  • CrossRef
  • Google Scholar

• 258

  SuHLiangZWengSSunCHuangJZhangTet al. Mir-9-5p regulates immunometabolic and epigenetic pathways in B-Glucan-Trained immunity Via Idh3α. JCI Insight (2021) 6(9):e144260. doi: 10.1172/jci.insight.144260

  • CrossRef
  • Google Scholar

• 259

  ThaissCAZmoraNLevyMElinavE. The microbiome and innate immunity. Nature (2016) 535(7610):65–74. doi: 10.1038/nature18847

  • CrossRef
  • Google Scholar

• 260

  Zysset-BurriDCKellerIBergerLELargiaderCRWittwerMWolfSet al. Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration. NPJ Genom Med (2020) 5:34. doi: 10.1038/s41525-020-00141-0

  • CrossRef
  • Google Scholar

• 261

  KhanRSharmaARavikumarRParekhASrinivasanRGeorgeRJet al. Association between gut microbial abundance and sight-threatening diabetic retinopathy. Invest Ophthalmol Vis Sci (2021) 62(7):19. doi: 10.1167/iovs.62.7.19

  • CrossRef
  • Google Scholar

• 262

  KutsyrOMaestre-CarballaLLluesma-GomezMMartinez-GarciaMCuencaNLaxP. Retinitis pigmentosa is associated with shifts in the gut microbiome. Sci Rep (2021) 11(1):6692. doi: 10.1038/s41598-021-86052-1

  • CrossRef
  • Google Scholar

• 263

  KutsyrONoaillesAMartinez-GilNMaestre-CarballaLMartinez-GarciaMManeuVet al. Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation. Proc Natl Acad Sci U.S.A. (2021) 118(43):e2100566118. doi: 10.1073/pnas.2100566118

  • CrossRef
  • Google Scholar

• 264

  ParkerARomanoSAnsorgeRAboelnourALe GallGSavvaGMet al. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome (2022) 10(1):68. doi: 10.1186/s40168-022-01243-w

  • CrossRef
  • Google Scholar

• 265

  ScottPAKaplanHJMcCallMA. Prenatal exposure to curcumin protects rod photoreceptors in a transgenic Pro23his swine model of retinitis pigmentosa. Trans Vision Sci Technol (2015) 4(5):5. doi: 10.1167/tvst.4.5.5

  • CrossRef
  • Google Scholar

• 266

  EmotoYYoshizawaKUeharaNKinoshitaYYuriTShikataNet al. Curcumin suppresses n-Methyl-N-Nitrosourea-Induced photoreceptor apoptosis in sprague-dawley rats. In Vivo (2013) 27(5):583–90.

  • Google Scholar