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.
Highlights
Diabetic retinopathy (DR) is the most common and serious ocular complication [1]
We previously showed that IL17A injection in the vitreous cavity exacerbated diabetes-induced retinal microvascular lesions, activation and dysfunction of retinal Müller cells (RMCs), and apoptosis of retinal ganglion cells (RGCs) and that blocking IL-17A alleviated the diabetes-induced retinal abnormalities [10, 11]
Retinal microvascular lesions are alleviated in IL-17A-deficient diabetic mice As expected, retinas of Akita mice 12 weeks after the onset of diabetes showed increased number of leukocytes adhered to blood vessels (Fig. 1A), downregulated expression of the tight junction proteins occludin and zonula occludens-1 (ZO-1) (Fig. 1B), and enhanced dextran leakage from vessels (Fig. 1C), compared with respect to those of WT mice
Summary
Diabetic retinopathy (DR) is the most common and serious ocular complication [1]. In spite of the extensive research, the complex pathogenesis of DR has not been fully elucidated. It has been thought that DR manifests only with microangiopathic lesions, which are totally responsible for the loss of vision in diabetic patients [2]. In view of the current knowledge that during diabetes complex microvascular, neuronal, and glial abnormalities progressively disrupt retinal function and develop DR, DR is perceived as a neurovascular inflammatory disease [3,4,5,6]. The presence of high levels of inflammatory cytokines in the eye fluids of patients with DR has been observed, demonstrating a close correlation between inflammation and DR [7]. The present knowledge is basically limited to the role of inflammation driven by retinal glial cells (Müller cells, astrocytes and microglia) in DR. The role of adaptive immune reaction driven by T lymphocytes in DR and its underlying mechanism remain poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
