Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA.
FASEB J. 2023 Nov;37(11):e23277. doi: 10.1096/fj.202300893R.
Pathogenic Th17 cells are critical drivers of multiple autoimmune diseases, including uveitis and its animal model, experimental autoimmune uveitis (EAU). However, how innate immune signals modulate pathogenic Th17 responses remains largely unknown. Here, we showed that miR-338-3p endowed dendritic cells (DCs) with an increased ability to activate interphotoreceptor retinoid-binding protein (IRBP) -specific Th17 cells by promoting the production of IL-6, IL-1β, and IL-23. In vivo administration of LV-miR-338-infected DCs promoted pathogenic Th17 responses and exacerbated EAU development. Mechanistically, dual-specificity phosphatase 16 (Dusp16) was a molecular target of miR-338-3p. miR-338-3p repressed Dusp16 and therefore strengthened the mitogen-activated protein kinase (MAPK) p38 signaling, resulting in increased production of Th17-polarizing cytokines and subsequent pathogenic Th17 responses. In addition, methyltransferase like 3 (Mettl3), a key m6A methyltransferase, mediated the upregulation of miR-338-3p in activated DCs. Together, our findings identify a vital role for Mettl3/miR-338-3p/Dusp16/p38 signaling in DCs-driven pathogenic Th17 responses and suggest a potential therapeutic avenue for uveitis and other Th17 cell-related autoimmune disorders.
致病性 Th17 细胞是多种自身免疫性疾病（包括葡萄膜炎及其动物模型实验性自身免疫性葡萄膜炎（EAU））的关键驱动因素。然而，先天免疫信号如何调节致病性 Th17 反应在很大程度上仍是未知的。在这里，我们表明 miR-338-3p 通过促进 IL-6、IL-1β 和 IL-23 的产生，赋予树突状细胞（DCs）激活光感受器间视黄醇结合蛋白（IRBP）特异性 Th17 细胞的能力。LV-miR-338 感染的 DCs 的体内给药促进了致病性 Th17 反应并加重了 EAU 的发展。在机制上，双特异性磷酸酶 16（Dusp16）是 miR-338-3p 的分子靶标。miR-338-3p 抑制 Dusp16，从而增强丝裂原活化蛋白激酶（MAPK）p38 信号，导致 Th17 极化细胞因子的产生增加，并随后导致致病性 Th17 反应。此外，甲基转移酶样 3（Mettl3），一种关键的 m6A 甲基转移酶，介导了激活的 DCs 中 miR-338-3p 的上调。总之，我们的研究结果确定了 Mettl3/miR-338-3p/Dusp16/p38 信号在 DC 驱动的致病性 Th17 反应中的重要作用，并为葡萄膜炎和其他 Th17 细胞相关自身免疫性疾病提供了潜在的治疗途径。
