IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy

Abstract

Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.

Icariin alleviates uveitis by targeting peroxiredoxin 3 to modulate retinal microglia M1/M2 phenotypic polarization

“…Under different forms of stimulation involving LPS and IRBP, microglia become polarized towards the M1 phenotype accompanied by overexpression of TNF-α, COX-2 and NO/iNOS. Mounting evidence has demonstrated that accumulated inflammatory factors can result in retinal degeneration/damage and blindness [ 25 , 26 ]. Fortunately, we also found that ICA treatment polarized microglia from the M1 phenotype to the M2 phenotype, accompanied by overexpression of ARG1, CD206 and IL-10, which subsequently protected the retina.…”

Interleukin-17A attenuates photoreceptor cell apoptosis in streptozotocin-induced diabetic mouse model

“…It is well established that the overexpression of IL-17A exacerbates DR-like pathology by decreasing the function of Müller cells, promoting retinal endothelial cell and retinal ganglion cell death, leading to retinal inflammation, oxidative stress, and vascular permeability in DM animals [ 10 , 11 , 25–27 ]. However, we surprisingly observed that depletion of IL-17A in the retina inhibited Müller cell activation (also known as gliosis) and accelerated the death of photoreceptors.…”

Regulations of Retinal Inflammation: Focusing on Müller Glia

“…IL-17RA, as well as IL-17A, expresses in MG ( Qiu et al, 2016 ). Both can be induced by diabetes, which enhances the inflammatory Act1/TRAF6/IKK/NF-κB signaling pathway activation ( Qiu et al, 2016 ), and contributes to retinal ganglion cells (RGCs) apoptosis ( Qiu et al, 2021 ). Following antigen stimulation or activation by cytokines such as IL-1 and TNF-α, G-CSF and GM-CSF are produced and generated by different types of cells and promote the production of granulocytes or antigen-presenting cells (APC) ( Mehta et al, 2015 ).…”