嗜酸性粒细胞调控巨噬细胞促进类风湿关节炎缓解的作用及机制研究

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by erosive synovitis. Macrophage serves as a key effector cell in the development of synovitis by mediating chronic inflammation. Recent findings suggested that eosinophil could shift tissue macrophage toward M2 phenotype and promote the resolution of inflammation. Previously we have found that, the percentage of M2 macrophage in the peritoneal cavity of lineage specific eosinophil deficient ΔdblGATA mice was significantly decreased compared with wildtype control. After induction of collagen antibody-induced arthritis, ΔdblGATA mice developed more severe arthritis and bone erosion than the wildtype control, accompanied with increased neutrophil infiltration in the synovium. In contrast, the IL-5 transgenic mice, which have hypereosinophilia, developed a milder arthritis. Based on these findings, we would like to explore the effect of eosinophil on synovial macrophage polarization and migration of neutrophils through in vivo and in vitro studies. It is expected to examine the role of eosinophil in promoting the resolution of RA and its molecular mechanisms. By performing this project, we will be able to clarify the role of eosinophil in inflammation and autoimmunity and provide a new direction and strategy for RA therapy in clinic.

类风湿关节炎（RA）是以侵蚀性滑膜炎为特征的慢性自身免疫性疾病。巨噬细胞介导慢性炎症, 是RA滑膜炎的核心效应细胞。近年研究表明，嗜酸性粒细胞可诱导组织巨噬细胞向M2型极化，参与促进炎症缓解。我们前期研究发现，特异性嗜酸性粒细胞缺乏的ΔdblGATA小鼠腹腔M2型巨噬细胞比例较野生型对照鼠明显减少。在建立胶原抗体诱导性关节炎后，关节炎临床评分和骨破坏显著增加，滑膜中性粒细胞浸润增多。与此相反，高嗜酸性粒细胞血症的IL-5转基因小鼠的胶原抗体诱导性关节炎发病较对照鼠明显减轻。本项目拟在前期研究基础上，从调控滑膜巨噬细胞的角度，通过体外和体内两个层面，研究嗜酸性粒细胞对滑膜巨噬细胞极化的影响及对中性粒细胞迁移的作用，深入探讨嗜酸性粒细胞在促进RA炎症缓解中的作用及分子机制。本项目的完成将有助于进一步认识嗜酸性粒细胞在自身免疫和炎症中的作用，也为RA的临床治疗提供新思路和新策略。

类风湿关节炎（RA）是以侵蚀性滑膜炎为特征的慢性自身免疫性疾病。巨噬细胞介导慢性炎症, 是RA滑膜炎的核心效应细胞。近年研究表明，嗜酸性粒细胞可诱导组织巨噬细胞向M2型极化，参与促进炎症缓解，但嗜酸性粒细胞在RA中的作用尚不明确。本项目在前期工作基础上，首先研究了嗜酸性粒细胞缺乏以及过继转移嗜酸性粒细胞对关节炎小鼠病情及滑膜巨噬细胞极化状态的影响。我们发现，嗜酸性粒细胞缺乏的小鼠关节炎明显加重，滑膜M1型巨噬细胞增多，iNOS表达升高，而Arg1表达降低。在胶原诱导的关节炎小鼠的不同时间点过继转移嗜酸性粒细胞改善了小鼠关节炎临床评分，滑膜M2型巨噬细胞增多。体外实验发现，在巨噬细胞与不同比例的嗜酸性粒细胞共培养体系中，培养上清液TNFα、IL-6、IL-12水平降低，而TGF-β、IL-10、IL-13的水平升高，同时M1型巨噬细胞比例降低，M2型巨噬细胞比例升高，而在培养体系中加入抗IL-4和（或）抗IL-13抗体后可拮抗上述效应。综上，本项目从调控滑膜巨噬细胞的角度，通过体内和体外两个层面阐明了嗜酸性粒细胞通过分泌IL-4/IL-13等抗炎介质，调控巨噬细胞向M2型极化，诱导和促进RA 炎症缓解。