趋化因子CCL28在类风湿关节炎发病中的作用及其机制

Chemokine CCL28 is a ligand for chemokine receptor CCR10 and CCR3 and its role in the pathogenesis of rheumatoid arthritis (RA) is unknown. Recently, we found that the expression of CCL28 is up-regulated in synovial fluid and inflamed synovium of patients with RA and CCR10 expression on CD4+ T cells is markedly elevated in RA synovial fluid. Moreover, it has been shown that CCR3 expression on monocytes is significantly increased in synovial fluid of RA patients. Thus, we speculate that CCL28 may be involved in the synovial inflammation and bone erosion in RA. Firstly, we are to evaluate the in vitro migration of RA CD4+ T cells and monocytes stimulated by CCL28 and the effect of CCL28 on osteoclast differentiation and bone resorption. Secondly, recruitment by CCL28 of lymphocytes and monocytes in vivo to engrafted human RA synovial tissue will be examined in a SCID mouse chimera. Lastly, lentivirus-mediated RNA interference is used to determine suppressive effects of local CCL28 gene silencing on the onset and progression of collagen-induced arthritis in mice. This project is to clarify the role of CCL28 in RA synovial inflammation and joint destruction and provide new clues for basic study and immune therapy of RA.

趋化因子CCL28，受体为CCR10和CCR3，在类风湿关节炎（RA）发病中的作用尚不清楚。我们前期研究发现RA患者滑液和滑膜组织CCL28表达上调，滑液CD4+ T细胞高表达CCR10，另有报道RA患者滑液单核细胞CCR3表达增加，推测CCL28可能参与了RA滑膜炎症和骨质破坏。本课题拟通过体外实验探讨CCL28在RA患者CD4+ T细胞和单核细胞迁移以及单核细胞来源的破骨细胞分化和骨吸收中的作用与机制；通过人滑膜-SCID鼠嵌合模型在体研究CCL28在淋巴细胞和单核细胞向RA滑膜迁移中的作用；并利用慢病毒介导的RNA干扰技术研究局部CCL28基因沉默对小鼠胶原诱导的关节炎发病和进展的抑制作用。通过以上研究深入探讨CCL28在RA滑膜炎症和骨质破坏中的作用及其机制，为RA的基础研究和免疫治疗提供新的理论和实验依据。