CXCL16/CXCR6 and Their Roles in Autoimmune Arthritis

CXCL16/CXCR6 及其在自身免疫性关节炎中的作用

• 批准号: 7030944
• 负责人: SHUHUA HAN
• 金额: $ 32.96万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030944
• 关键词: B lymphocyte; cell cell interaction; cell migration; chemokine; chemokine receptor; disease /disorder etiology; flow cytometry; genetically modified animals; helper T lymphocyte; immunoregulation; inhibitor /antagonist; laboratory mouse; leukocyte activation /transformation; macrophage; polymerase chain reaction; receptor expression; rheumatoid arthritis; tissue /cell culture; transcription factor

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

尽管类风湿性关节炎（RA）的病因和发病机制非常复杂，但其病因和发病机制仍然不清楚。 调查。趋化因子在吸引和保留发炎关节中的白细胞方面发挥着关键作用。然而，细胞在关节中定位的精确机制尚不清楚。 该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，一种新发现的趋化因子CXCL16及其受体CXCR6在患有胶原诱导性关节炎（CIA）（一种RA动物模型）的小鼠关节中高表达。 CXCL16 是具有跨膜结构域的趋化因子家族的第二个成员。携带受体的细胞主要是Th1细胞，具有淋巴外组织归巢能力，并且在RA患者发炎的滑液中富集。用 CXCL16-Ig 融合蛋白治疗小鼠可显着改善 CIA。因此，我们假设CXCL16/CXCR6在自身免疫性关节炎的发病机制中发挥重要作用。该项目将重点研究调节 CXCL16/CXCR6 表达的机制以及 CXCL16/CXCR6 对 CXCL16/CXCR6 表达的贡献。 中央情报局的发起和发展。在 RA 等 Th1 介导的炎症性疾病中优先表达的趋化因子，如 CXCR3 和 CCR5，也将在 CIA 过程中进行比较研究，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，我们假设CXCL16/CXCR6可能介导受影响部位的T细胞、B细胞、巨噬细胞和其他细胞之间的相互作用。将研究 CXCL16/CXCR6 在介导 T 细胞-抗原呈递细胞中的作用。除了增强我们对类风湿关节中白细胞迁移的理解之外，这些研究预计还将提供有关趋化因子在调节中的功能的重要信息。 炎症反应期间淋巴细胞和巨噬细胞的激活和分化。该研究还将为设计治疗自身免疫性关节炎和其他自身免疫性疾病的抗炎药物的新靶点提供见解