胚胎和骨髓来源滑膜巨噬细胞在类风湿关节炎中的作用及CP-25对其调控机制

滑膜巨噬细胞(SM)参与类风湿关节炎(RA)滑膜病变，但SM的来源及在RA滑膜中确切作用尚不完全清楚。课题组前期研究发现，SM至少存在两种来源即胚胎期定植于关节滑膜的巨噬细胞(ESM)和骨髓来源的巨噬细胞(BMDM)，在关节炎小鼠和RA患者表现不同的细胞特性。芍药苷-6-氧-苯磺酸酯（CP-25）是课题组研制有治疗RA潜力的单体化合物，GRK2是其主要靶点，并初步发现CP-25能调控RA患者滑膜和CIA小鼠的ESM和BMSM。本课题利用基因工程小鼠模型，通过细胞示踪术、骨髓嵌合体模型系统等方法拟揭示：ESM包括卵黄囊和胎肝两种来源；ESM和BMDM的细胞特性及功能有显著差别且在RA病程中发挥不同作用；CP-25通过GRK2调控PGE2-EP4-cAMP-PKA-CREB信号通路恢复ESM和BMDM的平衡发挥治疗作用。本课题将为发现RA滑膜病变新机制和CP-25治疗作用新机制提供实验依据。

Synovial macrophages(SM) participate in the pathogenesis of rheumatoid arthritis(RA), while the origins and specific function of SM in RA is still elusive. Our previous experiments showed that there are at least two origins of SM， embryonic SM(ESM) and bone marrow-derived SM(BMSM), which show different cellular features in arthritis mice and RA patients. CP-25 is a potential compound for RA treatment, developing by our group. GRK2 is a target of CP-25, we also partially demonstrated that CP-25 could regulate ESM and BMSM in RA patients’ synovium and CIA mice. By using genetic engineering mice, cell-tracking system, chimeric mice model and MIT etc., this project is designed to prove: ESM stems from yac solk and fetal liver; ESM and BMSM have different cellular function and play diverse role in the development of RA; CP-25 exerts its therapeutical effect on RA by regulating GRK2-PGE2-EP4-cAMP-PKA-CREB pathway and restoring the balance between ESM and BMSM. This project will provide experimental foundation of identifying new pathological mechanism of RA synovitis and novel regulatory mechanism of CP-25.