IL-17A Exacerbates Diabetic Retinopathy By Impairing Muller Cell Function Via Act1 Signaling

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 Muller cells were used to mimic DR-like pathology.Diabetes induced retinal expression of IL-17A and IL-17 receptor A(IL-17RA)in Muller cells in contrast to ganglion cells.Further evidence demonstrated that retinal Muller 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 Muller 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 Muller 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 Muller cell functional impairment via Act1 signaling.