精氨酸代谢调控类风湿关节炎MDSC-Th17交互作用及小乌桂汤疗效机制研究

类风湿关节炎(RA)致残率高，骨破坏机制是拟解决的关键科学问题。申请者新近第一作者发表在Rheumatology的研究发现：髓源性抑制细胞（MDSC）与Th17交互作用形成恶性循环是RA骨破坏的重要病机，并且MDSC-Th17交互作用有赖于MDSC表达的精氨酸酶1，但具体调控机制尚不清楚；中药复方小乌桂汤临床治疗RA疗效确切，申请者前期研究发现小乌桂汤缓解骨破坏可能是通过抑制MDSC-Th17。综上提出假说：精氨酸代谢介导的MDSC-Th17交互作用是RA骨破坏的重要病机和小乌桂汤的作用靶点。本项目拟在前期研究基础上：①纳入RA患者分析精氨酸酶1与骨破坏的关系②体外Th17极化及体内MDSC移植实验阐明精氨酸代谢调控的机制③小乌桂汤干预的MDSC体外与Th17共培或体内移植到RA小鼠，探讨疗效机制。目标是阐明精氨酸代谢调控MDSC-Th17的机制及小乌桂汤疗效机制，为RA精准治疗提供靶点。

Rheumatoid arthritis (RA) is characterized by progressive joint destruction and disability, which is the key scientific issues to be solved. Recent progress published in Rheumatology by the applicant as the first author uncovers that Myeloid-derived suppressor cells (MDSC) interact with Th17 to form a vicious circle, which contribute to the uncontrolled bone destruction in RA. What`s more, MDSC-Th17 interaction depends on the arginase 1 expressed by MDSC. However, the mechanism of arginine metabolism in the regulation of MDSC-Th17 interaction is unclear; Traditional Chinese Medicine Xiaowugui Decoction has a good effect in the clinical treatment of RA. Our preliminary study indicate that Xiaowugui Decoction relieves the bones destruction of RA mice model, which is related to the inhibition of MDSC-Th17. Therefore, we hypothesize that MDSC-Th17 interaction mediated by arginine metabolism is an important pathogenesis of bone destruction in RA and the therapeutic target of Xiaowugui Decoction. Based on our previous work, this project intends to: ① Include RA patients to analyze the relationship between arginase 1 and bone destruction. ② Clarify the regulatory mechanism of arginine metabolism by in vitro Th17 polarization and in vivo MDSC transplantation assay. ③ Co-culture Th17 cells with Xiaowugui Decoction treated MDSC or transplant these MDSC in to RA mice model in vivo to clarify the therapeutic mechanism. The aim of this project is to reveal the mechanisms of arginine metabolism in regulating MDSC-Th17 interaction and clarify the therapeutic mechanism of Xiaowugui Decoction to provide novel target for precision treatment of RA.