STING/TMEM203在磨损颗粒激活巨噬细胞PRRs/TBK1信号通路引起人工关节无菌性松动中的作用机制

人工关节置换术是治疗终末期骨关节疾病的最有效方法，但术后假体无菌性松动严重制约了其远期疗效，迄今却无有效防治药物。申请人在德国留学期间及归国后国家自然科学基金资助下的研究发现：磨损颗粒激活巨噬细胞PRRs（TLRs、NLRs等）后产生促炎因子及M1型极化进而激活破骨细胞是引起假体无菌性松动的主要原因。最新研究发现：TBK1的激活是巨噬细胞PRRs被激活后产生促炎因子以及其极化的核心步骤，而STING/TMEM203复合物是调控TBK1激活的关键。本课题组近期发现磨损颗粒激活巨噬细胞PRRs后TBK1的表达明显上调，STING的磷酸化水平也显著上升，但STING/TMEM203在磨损颗粒激活巨噬细胞引起人工关节无菌性松动中的作用尚无文献报道。本研究将在以往基础上，通过体内外实验探讨STING/TMEM203在磨损颗粒激活巨噬细胞中的作用机制，为防治人工关节远期无菌性松动开辟新的思路。

Arthroplasty is the most effective method for the treatment of end-stage osteoarthropathy, while the long-term efficacy of artificial joints is limited largely due to aseptic loosening, and there is no any effective medicine to prevent yet. After conducting in-depth researches in Germany and in China under the support of several NSFC funds, the applicant found that the wear particles could activate macrophages via PRRs (such as TLRs, NLRs, etc.) to produce pro-inflammatory cytokines and induce M1 polarization, which were the main reasons for osteoclast activation and aseptic prosthesis loosening. The newest studies showed that TBK1 was crucial in the production of pro-inflammatory cytokines and the process of M1 polarization following PRRs activation of macrophages, and the activation of TBK1 could be regulated by STING/TMEM203 complex. Furthermore, the applicant found that in the process of macrophage PRRs activation induced by wear particles, TBK1 expression significantly rised, followed with up-regulation of STING phosphorylation. However, it remains unclear whether STING/TMEM203 has a role in aseptic joint loosening caused by wear particles activating macrophages. On the basis of previous researches, this project will explore the mechanism of STING/TMEM203 in the activation of macrophages induced by wear particles in vitro and in vivo, and provide a new horizon in the prevention and treatment of aseptic joint loosening.