m6A甲基化调控胶原诱导性关节炎小鼠MDSC功能变化的机制研究

髓源性抑制细胞（MDSC）是一种重要的免疫抑制细胞，但在类风湿性关节炎中的作用存在争议。m6A甲基化修饰通过影响细胞内RNA代谢，发挥重要调控作用。我们发现，胶原诱导性关节炎（CIA）小鼠发病早期MDSC具有较强抑制功能，而中晚期其抑制功能下降，MDSC的m6A甲基化水平和甲基化转移酶METTL3表达也出现同步变化；敲减或过表达METTL3可改变MDSC的抑制功能。我们推测，在CIA发病过程中，MDSC细胞m6A甲基化水平下降，进而降低其免疫抑制功能，不能有效控制炎症，导致疾病加剧。本项目将明确m6A甲基化转移酶对MDSC及亚群的调控作用；寻找m6A甲基化转移酶和读码器蛋白调控MDSC功能变化的分子机制，以及涉及的信号通路，并在临床标本加以验证；观察经m6A甲基化功能蛋白干预的MDSC对CIA的影响。本研究从m6A甲基化这一新的视角解释CIA小鼠MDSC功能变化，为阐明疾病机制提供新思路。

Myeloid-derived suppressor cells (MDSCs) are derived from the myeloid progenitors with immunosuppressive functions. It has been shown that MDSC populations are expanded in autoimmune diseases. Nevertheless, the role of MDSCs in this process is unclear, and contrasting studies show positive and negative roles for MDSCs in the regulation of disease progression. N6-methyladenosine (m6A) methylation, one of the most common RNA modifications, has been reported to execute important functions. We found that MDSC had a strong immunosuppressive capacity in the early stage of murine collagen induced arthritis (CIA), but the immunosuppressive capacity of MDSCs was down-regulated during the progression of CIA. Meanwhile, the levels of m6A methylation and methyltransferase METTL3 was significantly decreased in late-stage MDSC compared with that in early-stage MDSC. Overexpression of METTL3 could increase immunosuppressive capacity of MDSC. We speculated that the down-regulation of m6A methylation decreased immunosuppressive capacity of MDSC, which could not effectively control inflammatory response in the process of CIA, leading to the aggravation of the disease. In this study, we will further clarify the regulatory effect of m6A methyltransferase on MDSC and different subpopulations. The molecular mechanisms of m6A methyltransferase and m6A reader protein regulating MDSC function, as well as the involved signaling pathway, will be investigated. In addition, the effect of m6A methylation gene modified MDSC on the pathogenesis of CIA will be further observed. This project will understand MDSC function from the new perspective of m6A methylation modification, and provide novel ideas for disease mechanism.