p38α/MKP-1 信号轴在调控Th17细胞分化及自身免疫性关节炎中的作用研究

Rheumatoid arthritis （RA）and its mouse model, type II collagen-induced arthritis (CIA), are characterized by a Th17-dependent systemic and synovial tissue inflammation. Despite our increasing knowledge on T cell-intrinsic pathways in regulating Th17 cell differentiation and function, how the T cell-extrinsic upstream and downstream components regulate Th17 cell development and Th17-mediated vicious cycle in autoimmune arthritic inflammation remain unknown. Our published studies have established an important role of p38α/MKP-1 signaling axis in dendritic cells (DCs) in programming Th17 cell differentiation and function. In this grant application, we will employ two genetic mouse models with DC-specific and complete deletion of p38α or MKP-1 to explore the mechanisms of p38α/MKP-1 signaling axis in regulating Th17 cell differentiation and function and in the pathogenesis of Th17-dependent RA or CIA. These studies link p38α/MKP-1 signaling axis in DCs and target cells to Th17 cell development and Th17-dependent RA or CIA for the first time, which can be directly translated into new therapeutics against the Th17-dependent autoimmune diseases.

类风湿性关节炎（RA）及其小鼠模型-Ⅱ型胶原诱导性关节炎(CIA)是Th17细胞依赖的自身免疫性疾病。尽管人们对T细胞内在因素如何影响Th17细胞的分化及功能了解较多，但对其外在上下游因素如何调控Th17细胞的分化及Th17细胞依赖的自身免疫性关节炎鲜有报道。本申请人的前期研究表明，树突状细胞（DC）p38α/MKP-1信号轴在调控Th17细胞的分化和功能中发挥重要作用。本项目拟运用p38α和MKP-1 DC特异性基因敲除和全基因敲除小鼠，从正反两方面深入阐述 p38α/MKP-1信号轴调控Th17细胞的分化发育及Th17细胞依赖的RA或CIA的机制。本研究首次将DC及靶细胞p38α/MKP-1信号轴、Th17细胞的分化和功能与RA或CIA联系起来，研究成果将为以DC 或靶细胞p38α/MKP-1为靶点的Th17细胞依赖的自身免疫性疾病的临床治疗奠定理论基础。