Degenerative retinal diseases affect millions of people worldwide and can eventually lead to irreversible vision loss. Currently, the prevalence of degenerative retinal diseases such as AMD, DR or glaucoma is increasing year by year (1). It is estimated that around 288 million people worldwide will be affected by AMD by 2040 (2). The raw prevalence of blindness due to DR increased substantially between 1990 and 2015 due to the rising prevalence of type 2 diabetes (3). Additionally, more than 76 million people are estimated to have glaucoma globally (4). There is no effective treatment that can reverse these degenerative processes. Retinal neurons continue to withstand long-term light, stress and aging or other factors leading to degenerative changes. Even though healthy retinas can resist stress for decades, the risk of retinal dysfunction affected by the disease gradually increases (5). A large body of convincing evidence demonstrates that inflammatory factors have been qualified as an important role in retinal degeneration (6–9).

IL-17A is the first member of the IL-17 family to be identified because it is most closely related to human health and disease (10). IL-17A was screened out from subtracted cDNA library in 1993, and its binding receptor was first discovered in 1995 (11, 12). At present, IL-17A has been observed under different tissues and immunopathological conditions, such as autoimmune diseases, tumors or obesity (13). The expression level of IL-17A cytokines is closely related to the severity and progression of the disease in human neurodegenerative diseases (9, 14, 15). Clinically, it was found that the levels of IL-17A in the plasma and cerebrospinal fluid of Alzheimer’s disease patients were elevated (16, 17). In addition, dopaminergic neurodegenerative diseases, dyskinesias, and blood-brain barrier destruction in Il-17a ^-/- mice were all alleviated (18). Interestingly, Yang et al. (19) reported that IL-17A did not cause neuroinflammation aggression. Overexpression of IL-17A could also reduce the level of soluble Aβ in the mid-cerebrospinal fluid and hippocampus as well as improving glucose metabolism, which provided a more comprehensive basis for the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (19).

On the other hand, there are more and more researches on IL-17A in eye diseases. The activation of IL-17 pathway has become an important target of autoimmune uveitis, pathological neovascularization and other diseases (20–22). In fact, the mechanism of IL-17A is more complicated than simply causing inflammation. Its contribution to the specific conditions of health and disease has only just begun to be recognized. The role of IL-17A in retinal degenerative diseases is still unclear. Therefore, this article mainly reviews IL-17A and its role in retinal degenerative diseases.

In 1993, Interleukin (IL) -17A (formerly CTLA8) was described and named by Rouvier et al. for the first time (11, 23). Subsequently, IL-17 family has grown gradually, with six cytokine members from IL-17A to IL-17F. (24) In addition, there are five receptor subunits in the family, including IL-17RA to IL-17RE (25). Little is known about IL-17B to IL-17F, while IL-17A has been widely studied because it has the closest relationship with human health and disease. IL-17A is the primary cytokine in the IL-17 series, originally discovered to be produced by activated CD4 ⁺ memory T lymphocytes. Subsequently, it was later discovered that it can also be the product of CD8 ⁺ memory T lymphocytes (23, 26–28). Although most of IL-17A is produced by activated T lymphocytes, other inflammatory cells such as neutrophils, macrophages and even microglia may also be producers of IL-17A under certain circumstances (29–31). IL-17A is a key cytokine responsible for the recruitment, activation and migration of neutrophils, which can be combined with IL-17RC/IL-17RA on fibroblasts, endothelial cells and epithelial cells in the form of dimers to induce pro-inflammatory secretion of the medium (32, 33).

IL-17A is often considered as a bad character. Alzheimer’s disease (AD) is a neurodegenerative disease dominated by amyloid deposition in the brain. Recent studies have reported that IL-17A was involved in the early pathological process of AD, causing cognitive impairments and synaptic dysfunction (34) Neutralization of IL-17A restored the function of Aβ-induced neuroinflammation and memory impairment (35). Animal experiments have also confirmed that IL-17A functioned in the occurrence and development of Parkinson’s disease (PD). Dopaminergic neurodegeneration, dyskinesia, and BBB disruption were ameliorated in Il-17a-deficient mice (18). In addition, increased levels of IL-17A were detected in samples from both MS and ALS patients (15, 36). Likewise, IL-17A is playing an increasingly important role in inflammatory autoimmune and cardiovascular disease (37–39). Interestingly, on the other hand, Reed et al. demonstrated that IL-17A could improve social deficits in a mouse model of neurodevelopmental disorders (40). IL-17A even promoted wound healing, which not only providing antibacterial protection and pathogens elimination, but also encouraging the proliferation of corneal forming cells after injury (13, 41, 42). Therefore, the above findings suggest that IL-17A is not just an inflammatory factor. IL-17A may protect the body under certain circumstances, but in those with chronic or degenerative conditions, IL-17A tends to start causing disease.

IL-17A is mediated by IL-17F, which normally co-produces IL-17A with T helper 17 (Th17) cells. The percentage homology between IL-17A and IL-17F is 50%, and they are co-expressed on linked genes (10, 43). Nevertheless, IL-17A and IL-17F have similar biological activities but different functions. IL-17A is involved in autoimmunity, inflammation and tumorigenesis while IL-17F is mainly involved in the mucosal defense mechanism. What’s more, IL-17A has a stronger affinity for IL-17RA/RC complex so it can promote the induction of pro-inflammatory genes more than IL-17F. Studies showed IL-17F mRNA instead of IL-17A mRNA could be expressed on colonic epithelial cells (44). IL-17F has been found to be an effective target for the treatment of colitis because Il-17f^–/– mice may resist the development of colitis (45). Studies have shown that IL-17F is more highly expressed in psoriasis and spondyloarthritis than IL-17A (46). It was demonstrated that IL-17F had similar pathogenic effects as IL-17A in β-cell lines and pancreatic islets in type I diabetic mouse models (47). In addition, IL-17F may also be involved in systemic sclerosis fibrosis and vascular disease (48). Dual inhibition of IL-17A and IL-17F may be more effective than IL-17A alone in reducing disease pathological changes (49, 50).

Screening for IL-17A to identify homologous genes led to the discovery of IL-17B whose mRNA is strongly expressed in the adult digestive system (51). Zhou et al. (52). found that the concentration of IL-17B in adults and children with community-acquired pneumonia was significantly increased. In addition, the level of IL-17B in patients with lupus erythematosus was significantly higher than that in the control group, involving in the pathogenesis of the disease. At the same time, more and more evidences have proved that IL-17B/IL-17RB get trapped in the occurrence and poor prognosis of patients with malignant tumors such as pancreatic cancer, gastric cancer, lung cancer and breast cancer (53).

The uniqueness of IL-17C lies in its cell source: epithelial cells rather than CD4⁺ cells are the producer of IL-17C, whose receptor IL-17RE is expressed in Th17 cells and the epithelial cells themselves. New research showed that IL-17C maintained the autocrine cycle in the epithelium, thus inhibiting innate immune infection or binding to receptors to activate the adaptive immune response (54). The usage of anti-IL-17C antibodies could control skin inflammation in mouse models of psoriasis and atopic dermatitis (55, 56). In addition, inhibiting IL-17C or blocking IL -17 RE might be a new treatment for acute kidney injury (57). Other studies have shown that IL-17C mediated antibacterial effects on pseudomonas aeruginosa by interfering with iron absorption in the nasal epithelium (58).

IL-17D possessed the similarity of inducing increased expression of chemokines and cytokines with other members in family (59). Curiously, IL-17D has not been found in the synovial fluid or peripheral blood of patients with rheumatoid arthritis but detected in its nodules. In addition, IL-17D mRNA expression in the skin of psoriatic patients was surprisingly reduced. IL-17D induces anti-tumor effects by recruiting NK cells (60–62).

More and more evidences showed that IL-17E (IL-25)was a “barrier cytokine” whose expression depends on external environmental factors. It may cause inflammatory diseases, such as atopic dermatitis, inflammatory bowel illness or asthma when upregulating. IL-17E has been proved to stimulate the proliferation and metabolic activity of keratinocytes. Excessive secretion of IL-17E caused by irritant atopic dermatitis (63, 64).

In a word, members of the IL-17 family play a key role in inflammatory diseases, autoimmune diseases and cancer. It regards IL-17 family members and their receptors as potential targets for future drug treatments ( Figure 1 ).

The IL-17R family contains five receptor subunits:IL-17RA to IL-17RE. All receptor subunits are type I transmembrane proteins. IL-17RA is a founding member of the IL-17R family as well as the co-receptor used by several other IL-17 family ligands. They shared the common cytoplasmic motif called the similar expression of fibroblast growth factor and IL-17R (SEFIR) domain.

Besides, there existed nonconserved region called SEFIR-Extension” (SEFEX) (65). Unlike other IL-17 family receptors, IL-17RA contained another C/EBP β activation domain (CBAD), whose function was related to negative signal regulation (66). Therefore, IL-17RA had at least two structurally and functionally discontinuous signal regions in the cytoplasm to control downstream signal events.

The IL-17B signaling pathway is mainly reflected in cancer diseases. IL-17B in breast cancer cells activated ERK and NF-kB pathways and enhanced the expression of anti-apoptotic Bcl-2 family members (67, 68). AKT/GSK-3β/β-catenin signaling pathway was promoted by IL-17B/IL-17RB signaling pathway to up-regulate Sox2, Oct4 and Nanog proteins, inducing stem cell transformation and epithelial to mesenchymal transformation of gastric cancer and lung cancer cells (69, 70). There are still unknown about receptor of IL-17D and the ligand of IL-17RD. Currently, the signaling pathways regarding downstream of IL-17C are rarely reported (53).

Among the IL-17 family cytokines, the signaling pathways concerning about IL-17A and IL-17E are the most fully characterized. IL-17A transmits signals through the IL-17RA and IL-17RC receptor subunits. IL-17F and IL-17A/F heterodimers also bind to this receptor complex.

The initial binding of IL-17A to its receptor complex recruited the adaptor protein ACT1, which interacts through the shared SEFIR domain. The next step was ACT1 to identify and ubiquitinate different TNF-receptor–associated factor (TRAF) adaptors (71). The activation of TEAF6 drived the triggering of the classical TAK1/NF-κB pathway, c/EBPβor c/EBPδ transcription factors and MAPK/AP-1 pathway (23, 72–75). The IL-17R-ACT1 complex binded to MEKK3 and MEK5 via TRAF 4 to activate ERK5. IL-17 signaling promoted the regulation of post-transcriptional IL-17 target gene mRNA stability or controlled a variety of RNA binding proteins through ACT1- TRAF2- TRAF5 complex (including HuR and Arid5a) (13).

IL-17RB, the binding receptor of IL-17E, needs to combine with IL-17RA to form a complex to mediate the downstream signal cascade in target cells (76). The supplementation of TRAF6 was essential for IL-17E-mediated activation of the NF-kB pathway (72). The activation of MAPKs may depend on TRAF4 (77). In addition, IL-17E has been also shown to activate the Act1-JAK1/2-STAT3 pathway, leading to the proliferation of keratinocytes and the production of inflammatory cytokines and chemokines in mouse skin (63).

Many regulators amplify or inhibit inflammation mediated by IL-17, respectively. Understanding its mechanism of action may provide strategies for designing new interventions to treat IL-17-mediated signals and inflammation ( Figure 1 ).

The retina is a tissue with immune properties, whose blood-retinal barrier and immunosuppressive microenvironment can maintain its homeostasis. In addition to physical barrier defenses, the retina is also protected and monitored by autoimmunity, namely microglia and the complement system (78). Ageing increases the risk of various retinal degenerative diseases, such as age-related macular degeneration, diabetic retinopathy, and glaucoma. All age-related retinal diseases have two common features:destruction of retinal homeostasis and low-grade chronic inflammation (79–81).

Resident microglia can be regarded as the immune guards of the retina. Inflammatory factors recruited by microglia accumulated in the damaged layer play a crucial role in the pathological changes (79, 80, 82). Drusen, the pathological marker of AMD, attracted macrophages and microglia (83, 84). The patients with geographic atrophy also showed microglia that positively swallowed photoreceptor fragments (85). It displayed that activation of microglia and macrophage were early and long-term chronic features in the pathogenesis of AMD (86). In human glaucoma, the activated microglia morphology was found in the optic nerve head and the choroidal retinal area adjacent to the optic nerve head (87). In addition, microglia expressed TNF-α and several metalloproteinases including MMP-1, MMP-2, MMP-3 and MMP-14, which were significantly increased during optic neuropathy (88). Therefore, activation of microglia may disrupt tissue stability during the early changes in the glaucoma disease process. Zeng et al. (89)deeply studied the different stages of 21 diabetic retinopathy patients’ eyes, and found that the neovascularization was very severely surrounded by microglia. Reactive microglia participated in all stages of diabetic retinopathy, even promoting its evolution to a proliferative state (89).

The retina has a complement regulation system. Actually, microglia, retinal pigment epithelial cells (RPE) and neurons in the retina express various complement and complement regulators (78, 90, 91). Under physiological conditions, retinal cells always expressed relatively high levels of complement regulators (CFH, C1INH, and CD59) and low levels of complement proteins (such as C1q, c3, and CFB) (92–95). Oxidative stress and inflammation attenuated the expression of complement inhibitors but increased the expression of complement components during aging (79, 92, 94–96). It means that the complement system may function in the immune defense of the retina. Age-related oxidative damage could directly regulate the expression of retinal cell complement. For example, oxidized photoreceptor outer segments not only reduced the expression of complement inhibitor CFH, but also strengthened the expression of CFB in RPE cells (97, 98). On the other hand, the change of the immunosuppressive microenvironment was able to interfere with the production of various complement regulators (C4bp, C1INH, DAF, and CD59) by RPE and microglia. In addition, the inflammatory factors released by subretinal macrophages may up-regulate the expression of complement protein in RPE cells (92, 99) ( Figure 2 ).

Currently, IL-17A is the factor most closely related to human health and disease in the IL-17 family. There is a synergistic effect between the development and progression of various retinal degenerative diseases and the imbalance of IL-17A. IL-17A not only participates in inflammatory pathogenicity, but also induces innate immune defense. The functions of IL-17A are more diverse than originally discovered. We still lack understanding of the role of IL-17A in tissue damage. With age, the immune privilege mediated by the retina may gradually weaken and disappear. The reduction in passive protection makes the retina more vulnerable to damage such as oxidative stress in AMD, hyperglycemia in diabetes and ocular hypertension in glaucoma ( Figure 3 ). It is necessary to further study how IL-17A interacts with different cells and cytokines in the retina to find better targets and pathways. In the future, intravitreal injection or non-invasive eye drop nanomaterials can be used to encapsulate IL-17 neutralizing antibodies as new treatment methods. Treatment strategies aimed at reducing the production of inflammatory factors may have a beneficial impact on the management of retinal degenerative diseases.

HZ wrote the manuscript. XS provided support, supervised, and edited the manuscript. All authors read and approved the final manuscript.

This study received by support from the National Natural Science Foundation of China (No. 82171076).

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

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