CXCL16/CXCR6 and Their Roles in Autoimmune Arthritis

类风湿性关节炎(RA)的病因和发病机制仍不清楚 调查。趋化因子在吸引和保留炎症关节中的白细胞方面起着关键作用。然而，细胞在关节中定位的确切机制尚不清楚。 这个项目的长期目标是了解自身免疫性疾病背景下非淋巴组织中细胞运输和炎症反应的机制。最近，我们发现新近发现的趋化因子CXCL16及其受体CXCR6在类风湿关节炎(RA)动物模型胶原诱导性关节炎(CIA)小鼠关节中高表达。CXCL16是趋化因子家族中具有跨膜结构域的第二个成员。承载受体的细胞主要是Th1细胞，具有淋巴组织外归巢潜能，在类风湿关节炎患者炎症的滑液中富含。用CXCL16-LG融合蛋白治疗小鼠可显著改善CIA。因此，我们推测CXCL16/CXCR6在自身免疫性关节炎的发病机制中起重要作用。本项目将重点研究CXCL16/CXCR6表达的调节机制以及CXCL16/CXCR6在 中央情报局的成立和发展。CXCR3和CCR5等Th1介导的炎症性疾病中优先表达的趋化因子也将在CIA过程中作为对比研究进行研究，以进一步阐明CXCL16/CXCR6在CIA发病机制中的作用。此外，由于CXCL16作为膜趋化因子的独特结构及其表达模式，我们推测CXCL16/CXCR6可能介导了病变部位T细胞、B细胞、巨噬细胞和其他细胞之间的相互作用。我们将研究CXCL16/CXCR6在介导T细胞-抗原提呈细胞中的作用。除了加强我们对类风湿关节中白细胞迁移的了解外，这些研究有望提供有关趋化因子在调节 炎症反应中淋巴细胞和巨噬细胞的激活和分化。这项研究还将为设计抗炎药治疗自身免疫性关节炎和其他自身免疫性疾病提供新的靶点。

The etiology and pathogenesis of rheumatoid arthritis (RA) remain obscure despite intense investigation. Chemokines play a critical role in attracting and retaining leukocytes in the inflamed joints. However, the precise mechanism for cell positioning in the joints is unclear. The long-term goal of this project is to understand the mechanism of cell trafficking and inflammatory responses in nonlymphoid tissues in the settings of autoimmune diseases. Recently we have found that CXCL16, a newly identified chemokine, and its receptor, CXCR6, are highly expressed in the joints of mice with collagen-induced arthritis (CIA), an animal model of RA. CXCL16 is the second member of the chemokine family with a transmembrane domain. The receptor-bearing cells are mainly Th1 cells, display extralymphoid tissue homing potential and are enriched in inflamed synovial fluid of RA patients. Treatment of mice with CXCL16-lg fusion protein significantly ameliorates CIA. Thus, we hypothesize that CXCL16/CXCR6 play an important role in the pathogenesis of autoimmune arthritis. This project will focus on the mechanisms that regulate CXCL16/CXCR6 expression and the contribution of CXCL16/CXCR6 to the initiation and progression of CIA. Chemokines that are preferentially expressed in Th1-mediated inflammatory disorders like RA, such as CXCR3 and CCR5, will also be investigated during the course of CIA as comparative studies to further elucidate the role of CXCL16/CXCR6 in the pathogenesis of CIA. In addition, we hypothesize that CXCL16/CXCR6 may mediate interactions among T cell, B cells, macrophages and other cells in the affected sites because of the unique structure CXCL16 as a membrane chemokine and its expression pattern. The role of CXCL16/CXCR6 in mediating T cell-antigen presenting cells will be studied. Aside from enhancing our understanding of leukocyte migration in rheumatoid joints, these studies are expected to provide important information regarding chemokine functions in regulating activation and differentiation of lymphocytes and macrophages during inflammatory responses. The study will also provide insights into new targets for designing anti-inflammatory agents in autoimmune arthritis and other autoimmune diseases