Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.
FASEB J. 2019 Dec;33(12):13951-13965. doi: 10.1096/fj.201901446R. Epub 2019 Oct 23.
Pathogenic T helper (T)17 cells are key mediators of autoimmune diseases such as uveitis and its animal model, experimental autoimmune uveitis (EAU). However, the contribution of microRNAs (miRs) to the intrinsic control of pathogenic T17 cells in EAU remains largely unknown. Here, we have reported that miR-223-3p was significantly up-regulated in interphotoreceptor retinoid-binding protein-specific T17 cells, and its expression was enhanced by IL-23-signal transducer and activator of transcription 3 signaling. Knockdown of miR-223-3p decreased the pathogenicity of T17 cells in a T-cell transfer model of EAU. Mechanistic studies showed that miR-223-3p directly repressed the expression of forkhead box O3 (FOXO3), and FOXO3 negatively regulated pathogenic T17 cell responses partially suppression of IL-23 receptor expression. Thus, our results reveal an important role for miR-223-3p in autoreactive T17 cell responses and suggest a potential therapeutic avenue for uveitis.-Wei, Y., Chen, S., Sun, D., Li, X., Wei, R., Li, X., Nian, H. miR-223-3p promotes autoreactive T17 cell responses in experimental autoimmune uveitis (EAU) by inhibiting transcription factor FOXO3 expression.
致病性辅助性 T 细胞 17（T helper 17，T17）细胞是葡萄膜炎等自身免疫性疾病的关键介质，其动物模型为实验性自身免疫性葡萄膜炎（E uveitis，EAU）。然而，miRNAs（microRNAs）在 EAU 中对致病性 T17 细胞的固有调控中的作用在很大程度上尚不清楚。本研究报道，miR-223-3p 在光感受器间维生素 A 结合蛋白特异性 T17 细胞中显著上调，其表达受 IL-23 信号转导和转录激活因子 3（signal transducer and activator of transcription 3，STAT3）信号增强。miR-223-3p 的敲低降低了 EAU T 细胞转移模型中 T17 细胞的致病性。机制研究表明，miR-223-3p 可直接抑制叉头框蛋白 O3（forkhead box O3，FOXO3）的表达，而 FOXO3 部分负调控致病性 T17 细胞反应，下调 IL-23 受体表达。因此，本研究结果揭示了 miR-223-3p 在自身反应性 T17 细胞反应中的重要作用，并为葡萄膜炎的治疗提供了新的靶点。
