AT1R通过GRK2/β-arrestin2信号调控骨髓源滑膜巨噬细胞M1极化促进类风湿关节炎的机制

滑膜巨噬细胞（SM）异常浸润是类风湿关节炎（RA）重要病理表现。研究表明骨髓来源SM（BMSM）与血管紧张素Ⅱ1型受体（AT1R）均可促进RA进展，但内在联系不明。申请人发现ERK1/2通路活化可促进巨噬细胞M1极化；AT1R对BMSM极化具有调控作用；GRK2和β-arrestin2与AT1R存在相互作用，参与调控AT1R信号转导。基于此提出假说：活化的AT1R与GRK2结合后招募β-arrestin2使ERK1/2磷酸化，促进BMSM M1极化。研究内容如下：AT1R表达与RA炎症指标和BMSM浸润的相关性；在动物模型中拮抗或过表达AT1R，明确其对BMSM极化及病程的影响；在GRK2和β-arrestin2敲除小鼠及二者沉默/过表达细胞株中，阐明AT1R促进BMSM M1极化介导RA进程的机制。通过揭示AT1R对BMSM M1极化的调控机制，为发现RA新的病理机制及治疗策略提供依据。

Abnormal infiltration of synovial macrophages (SM) is an important pathological manifestation of rheumatoid arthritis (RA). It is already reported that both bone marrow-derived SM (BMSM) and angiotensin II type 1 receptor (AT1R) can promote the progression of RA, but the internal connection is unknown. We find that ERK1/2 pathway activation can promote macrophage M1 polarization; AT1R has a regulatory effect on BMSM polarization; both GRK2 and β-arrestin2 interact with AT1R and participate in the AT1R cell signalling. We hypothesize that activated AT1R could bind with GRK2 and recruit β-arrestin2 which leads to ERK1/2 phosphorylation and finally promote BMSM M1 polarization. This project intends to study the AT1R expression in RA synovium and analyze its correlation with inflammation indicators and BMSM infiltration. Furthermore, we plan to antagonize or overexpress AT1R in the RA animal model to clarify the effects of AT1R on BMSM polarization and RA progression. Finally, we will knockout or overexpress GRK2 and β-arrestin2 in mice and RAW 264.7 cells to elucidate the mechanism of AT1R-induced BMSM M1 polarization that promotes the pathogenesis of RA. The planned steps to explain the underlying role of AT1R in BMSM M1 polarization will provide a basis to investigate new pathological mechanisms of RA and to explore new treatment strategies for RA.