Journal Article

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

Mao, Ping-An, Liu, Qing-Huai, Qiu, Ao-Wang, Bian, Zheng

2016

Overview

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. Ins2 Akita (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. Diabetes: Investigating inflammatory mechanisms behind diabetic blindness 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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 14/19 / 64/60 / 692/308/1426 / 692/308/575 / 82/80 / 96/2 / Adaptor Proteins, Signal Transducing - immunology / Animals / Biomedicine / Cells, Cultured / Diabetic Retinopathy - immunology / Diabetic Retinopathy - pathology / Ependymoglial Cells - immunology / Ependymoglial Cells - pathology / Interleukin-17 - immunology / Male / Medical Biochemistry / Mice / Mice, Inbred C57BL / Molecular Medicine / Original / original-article / Rats / Retina - immunology / Retina - pathology / Signal Transduction / Stem Cells