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.
Department of Medicine/Hematology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
FASEB J. 2023 Mar;37(3):e22803. doi: 10.1096/fj.202201548R.
Methyltransferase like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, has been implicated in various biological and pathological processes including immune responses. However, the functions and mechanisms of METTL3 in pathogenic T helper (Th)17 cells are poorly understood. Here we found significantly decreased METTL3 expression along with reduced m6A levels in eyeballs and T cells of experimental autoimmune uveitis (EAU). Overexpression of METTL3 ameliorated the development of EAU and suppressed pathogenic Th17 cell responses in vivo and in vitro. Mechanistically, METTL3 promoted the expression of absent, small, or homeotic-like 1 (ASH1L) via enhancing its stability in a YT521-B homology domain containing 2 (YTHDC2)-dependent manner, which further decreased the expression of IL-17 and IL-23 receptor (IL-23R), resulting in reduced pathogenic Th17 responses. Together, our data reveal a pivotal role of METTL3 in regulating pathogenic Th17 responses, which may contribute to human uveitis therapy.
甲基转移酶样蛋白 3（METTL3）是一种主要的 N6-甲基腺苷（m6A）甲基转移酶，参与多种生物学和病理学过程，包括免疫反应。然而，METTL3 在致病性辅助性 T 细胞 17（Th17）细胞中的功能和机制尚不清楚。在这里，我们发现实验性自身免疫性葡萄膜炎（EAU）眼组织和 T 细胞中 METTL3 的表达显著降低，m6A 水平也降低。METTL3 的过表达可改善 EAU 的发展，并在体内和体外抑制致病性 Th17 细胞反应。在机制上，METTL3 通过 YT521-B 同源结构域 2（YTHDC2）依赖性方式增强其稳定性，从而促进缺失、小或同源盒样 1（ASH1L）的表达，进而降低 IL-17 和 IL-23 受体（IL-23R）的表达，导致致病性 Th17 反应减少。总之，我们的数据揭示了 METTL3 在调节致病性 Th17 反应中的关键作用，这可能有助于人类葡萄膜炎的治疗。
