IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling

Abstract

Diabetic retinopathy (DR), one of the most serious complications of diabetes, has been associated with inflammatory processes. We have recently reported that interleukin (IL)-17A, a proinflammatory cytokine, is increased in the plasma of diabetic patients. Further investigation is required to clarify the role of IL-17A in DR. Ins2Akita (Akita) diabetic mice and high-glucose (HG)-treated primary Müller cells were used to mimic DR-like pathology. Diabetes induced retinal expression of IL-17A and IL-17 receptor A (IL-17RA) in Müller cells in contrast to ganglion cells. Further evidence demonstrated that retinal Müller cells cultured in vitro increased IL-17A and IL-17RA expression as well as IL-17A secretion in the HG condition. In both the HG-treated Müller cells and Akita mouse retina, the Act1/TRAF6/IKK/NF-κB signaling pathway was activated. IL-17A further enhanced inflammatory signaling activation, whereas Act1 knockdown or IKK inhibition blocked the downstream signaling activation by IL-17A. HG- and diabetes-induced Müller cell activation and dysfunction, as determined by increased glial fibrillary acidic protein, vascular endothelial growth factor and glutamate levels and decreased glutamine synthetase and excitatory amino acid transporter-1 expression, were exacerbated by IL-17A; however, they were alleviated by Act1 knockdown or IKK inhibition. In addition, IL-17A intravitreal injection aggravated diabetes-induced retinal vascular leukostasis, vascular leakage and ganglion cell apoptosis, whereas Act1 silencing or anti-IL-17A monoclonal antibody ameliorated the retinal vascular damage and neuronal cell apoptosis. These findings establish that IL-17A exacerbates DR-like pathology by the promotion of Müller cell functional impairment via Act1 signaling. The increase in a cytokine at high glucose concentrations impairs cellular activity in the retina, increasing the chances of blindness. A serious complication of diabetes is diabetic retinopathy (DR), a disease of the retina that results in impairment or loss of vision, but the inflammatory mechanisms behind DR remain unclear. Ao-Wang Qiu, Zheng Bian, Ping-An Mao and Qing-Huai Liu at Nanjing Medical University, China, investigated the role of a protein called interleukin-17A (IL-17A), which is implicated in autoimmune diseases. Using a mouse strain with DR, the team found that IL-17A was increased in certain cells responsible for maintaining a healthy retina. IL-17A increase caused retinal inflammation, impaired cell functioning and killed neuronal cells, accelerating DR progression. Disrupting the signalling pathway involved in IL-17A action alleviated symptoms in mice.