Retinal Müller Cell-Released Exosomal MiR-92a-3p Delivers Interleukin-17A Signal by Targeting Notch-1 to Promote Diabetic Retinopathy.

Purpose: Inflammatory processes have been involved in diabetic retinopathy (DR). Interleukin (IL)-17A, a pro-inflammatory cytokine, is associated with DR occurrence and development. However, mechanisms underlying the IL-17A impact on DR need further investigations. Herein, we show that exosomal miRNA delivers IL-17A signal from Müller cells (MCs) to retinal ganglion cells (RGCs) to facilitate DR. Methods: Exosomes isolated from primarily cultured MCs were identified and high-throughput sequencing was used to indicate differentially expressed miRNAs in the exosomes. Targeting relationship of miR-92a-3p and Notch-1 was determined by dual-luciferase reporter assay. MCs were treated with high glucose (HG), IL-17A, anti-IL-17A antibody, miR-92a-3p inhibitor, or/and miR-92a-3p mimic, and exosomes derived from MCs with the various treatments were applied to primary RGCs. DR mice were induced by streptozotocin (STZ) and subjected to intravitreal injection. Results: Expression of miR-92a-3p in exosomes derived from MCs with IL-17A treatment in either the absence or the presence of HG was upregulated, and the IL-17A effect was blocked by anti-IL-17A antibody. The exosomes derived from IL-17A-treated MCs downregulated Notch-1 expression in recipient RGCs and increased the neuronal death. These effects of IL-17A were suppressed by miR-92a-3p inhibitor but enhanced by miR-92a-3p mimic. In STZ mice, intravitreal administration of exosomes derived from IL-17A-treated MCs downregulated retinal Notch-1 expression and increased RGC apoptosis. These IL-17A effects were hindered by miR-92a-3p inhibitor. Conclusions: MC-released exosomal miR-92a-3p transmits IL-17A signal by inhibiting the target Notch-1 to accelerate DR progression. An intravitreal administration of exosomes containing miR-92a-3p inhibitor may become a potential therapeutic strategy for DR.