Qiu Ao-Wang, Wang Ning-Yu, Yin Wen-Jie, Zhu Zhao-Qi, Liu Qing-Huai, Zhang Wei-Wei
Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Invest Ophthalmol Vis Sci. 2025 Jan 2;66(1):1. doi: 10.1167/iovs.66.1.1.
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.
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.
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.
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.
炎症过程与糖尿病视网膜病变（DR）有关。白细胞介素（IL）-17A是一种促炎细胞因子，与DR的发生和发展相关。然而，IL-17A对DR影响的潜在机制需要进一步研究。在此，我们表明外泌体微小RNA（miRNA）将IL-17A信号从米勒细胞（MCs）传递至视网膜神经节细胞（RGCs），以促进DR的发展。
对从原代培养的MCs中分离出的外泌体进行鉴定，并使用高通量测序来指示外泌体中差异表达的miRNA。通过双荧光素酶报告基因检测确定miR-92a-3p与Notch-1的靶向关系。用高糖（HG）、IL-17A、抗IL-17A抗体、miR-92a-3p抑制剂或/和miR-92a-3p模拟物处理MCs，并将经各种处理的MCs来源的外泌体应用于原代RGCs。通过链脲佐菌素（STZ）诱导建立DR小鼠模型并进行玻璃体内注射。
在不存在或存在HG的情况下，经IL-17A处理的MCs来源的外泌体中miR-92a-3p的表达上调，且抗IL-17A抗体可阻断IL-17A的作用。经IL-17A处理的MCs来源的外泌体下调受体RGCs中Notch-1的表达并增加神经元死亡。miR-92a-3p抑制剂可抑制IL-17A的这些作用，而miR-92a-3p模拟物则增强这些作用。在STZ诱导的小鼠中，玻璃体内注射经IL-17A处理的MCs来源的外泌体可下调视网膜Notch-1的表达并增加RGC凋亡。miR-92a-3p抑制剂可阻碍IL-17A的这些作用。
MCs释放的外泌体miR-92a-3p通过抑制靶标Notch-1传递IL-17A信号，从而加速DR进展。玻璃体内注射含有miR-92a-3p抑制剂的外泌体可能成为DR的一种潜在治疗策略。
