Chemerin/ChemR23轴对RA中树突状细胞迁移的影响及Resolvin E1的调控

Rheumatoid arthritis (RA) is the most common inflammatory arthritis. Both innate and adaptive immunity and their corresponding effector cells and cytokines contribute to the mutiple pathogenic mechanisms in RA. As the bridge connecting innate and adaptive immunity, The migration of Dendritic cells(DCs) is important for RA, However,utill now, little effort had been put on the role of the migration of DCs is important for RA. Prior sudies showed that Chemerin/ChemR23 play an important role in control of DCs migration and related to the development of autoimmune diseases.Resolvin E1(RvE1), another ligand of ChemR23, is found to inhibit the migration of DCs and protect autoimmune diseases. So, in this study, we aim to investigate the effect of RvE1 on DCs in RA, hoping to find out a method to suppress the migration and other functions of DCs,and retrieving DC homeostasis.This may inaugurate a new way to control RA.

类风湿关节炎（rheumatoid arthritis，RA）是最常见的炎性关节病。树突状细胞(Dendritic Cells, DCs)在炎性介质刺激下迁移至局部淋巴结将抗原递呈初始T细胞是启动免疫应答的中心环节，在RA发病中起重要作用。研究发现Chemerin/ChemR23促进DC迁移，且与自身免疫病发病相关。ChemR23的另一配体resolvin E1（RvE1）可抑制DCs的迁移，且可阻止自身免疫病发生。因此我们推测RvE1可能通过与chemerin竞争性结合受体ChemR23，阻断Chemerin/ChemR23通路，抑制RA中的DCs的迁移阻止RA发病。本课题拟探讨RvE1治疗对RA模型小鼠关节炎病情、模型小鼠中DCs细胞体内体外迁移能力以及参与DCs迁移关键分子Chemerin/ChemR23表达的影响，进一步阐明DCs迁移在RA发病中的作用。

本课题组探讨Chemerin/ChemR23抑制剂Resolvin E1（RvE1）对RA模型小鼠中DCs迁移能力、关节炎病情的影响。课题组前期经过多次重复实验发现RvE1未明显降低CIA小鼠关节炎发病率，且未有效减轻CIA小鼠的关节肿胀程度，且多次体外研究发现RvE1对体外培养的骨髓源性DC（BMDCs）迁移及表面趋化因子受体ChemR23表达并无影响。.同时课题组观察到硫酸羟氯喹（HCQ）抑制RA发病可能与调控RA中DC功能有关，结果总结如下：.1.临床研究发现：与健康人比较，RA患者外周血DC亚群浆样DC（pDCs）和髓样DC（mDCs）明显升高。HCQ可明显抑制RA患者血清刺激的DCs表型成熟、分泌炎症因子干扰素-α（IFN-α）以及表面趋化因子受体CXCR4表达。.2.通过建立CIA模型，发现HCQ治疗可降低关节炎发病率，推迟发病时间，减轻关节肿胀程度及关节病理损伤程度。HCQ治疗后CIA模型小鼠淋巴结中DCs及其亚群mDCs和pDCs表达显著降低，HCQ治疗可抑制CIA模型小鼠LN中DCs表面趋化因子受体CCR7以及共刺激分子表达。.3.体外培养BMDCs，发现HCQ显著抑制LPS催熟BMDCs趋化因子CCL21分泌、趋化因子受体CCR7、CXCR4表达及体外迁移；且HCQ显著抑制LPS刺激的BMDCs表面共刺激分子表达，以及炎症因子分泌。.为了明确HCQ调控RA中DC功能的具体分子机制，本课题进行了研究，总结如下：.1.HCQ单抑制TLR9激动剂CpG-DNA刺激的BMDCs分泌IL-12p70，对其他TLRs激动剂刺激DCs分泌IL-12p70无影响。.2.临床研究发现与健康人血清比较，RA患者血清刺激的DCs表达TLR9明显升高，HCQ可显著抑制RA患者血清刺激的DCs表达TLR9。.3.与健康小鼠比较，CIA模型小鼠淋巴结DCs表达TLR9显著升高，HCQ治疗可下调CIA模型小鼠淋巴结DCs表达TLR9表达。.4.TLR9基因敲除后CIA模型小鼠关节炎发病时间延迟，关节肿胀程度减轻。TLR9基因敲除CIA小鼠淋巴结中DCs表达显著下降，其表面趋化因子受体CCR7、CXCR4及共刺激分子CD86表达显著下降。.上述结果提示HCQ可靶向TLR9抑制DCs迁移和成熟进而阻止RA发病及进展，这为TLR9抑制剂治疗RA及自身免疫病提供依据。