Cyclophilin-CD147 interaction in autoimmune arthritis

项目摘要/摘要 自身免疫性关节炎中的嗜环素和CD147 包括类风湿性关节炎(RA)在内的自身免疫性疾病的靶器官开始炎性破坏 随着效应细胞从微循环中迁出。抑制炎性白细胞 渗出对RA关节损伤有保护作用。然而，人们并不清楚它是如何 免疫细胞进入关节，以及白细胞重新聚集到滑膜的过程是如何 受监管的。白细胞转运的主要调节因子是趋化因子，这是一类趋化因子家族。 控制细胞迁移和黏附的物质。另一类不太受重视的趋化药物是 亲环素，一组高度丰富的细胞蛋白，主要是已知的细胞内受体 免疫抑制药环孢素A，也发挥胞外活性。例如，亲环素A 是一种对人类T淋巴细胞、嗜酸性粒细胞、单核细胞和中性粒细胞有效的趋化剂。我们的研究 鉴定了CD147，以前被认为是细胞外基质金属蛋白酶(MMPs)的诱导物，AS 胞外亲环素的细胞表面受体。然而，嗜环素和CD147在白细胞中的作用 生理或病理条件下的贩运和招募尚不清楚。我们现在建议 用胶原诱导性关节炎(CIA)研究这些蛋白在自身免疫性关节炎中的作用 类风湿性关节炎小鼠模型。将致力于实现以下具体目标： 目的1：用改良的环孢素A干预减轻CIA炎症反应； 目的2：研究细胞外嗜环素在CIA发病中的趋化作用； 目的3：评价CD147的趋化作用与其诱导基质金属蛋白酶的活性对CIA的作用 发病机制。 这些研究的结果将提供关于控制白细胞贩运的机制的信息 类风湿性关节炎，并将有助于识别和测试治疗试剂，通过对抗白细胞 渗出和减少基质金属蛋白酶的产生，可以防止炎症反应，也可以保护关节 即使在免疫反应已经产生的情况下，组织也会受到自身免疫性炎症的攻击。

PROJECT SUMMARY/ABSTRACT Cyclophilins and CD147 in autoimmune arthritis Inflammatory destruction of target organs in autoimmune diseases, including rheumatoid arthritis (RA), begins with the emigration of effector cells from the microcirculation. Suppression of inflammatory leukocyte extravasation could provide protection against joint damage in RA. However, it is not well understood how immune cells gain access to the joints, and how the process of leukocyte recruitment to the synovium is regulated. The main regulators of leukocyte trafficking are chemokines, a family of chemoattracting cytokines that control cell migration and adhesion. Another, less appreciated, class of chemotactic agents are cyclophilins, a group of highly abundant cellular proteins mostly known as intracellular receptors for immunosuppressive drug, cyclosporine A, but also exerting extracellular activities. For example, cyclophilin A is a potent chemotactic agent for human T lymphocytes, eosinophils, monocytes, and neutrophils. Our studies identified CD147, previously characterized as an inducer of extracellular matrix metalloproteinases (MMPs), as a cell surface receptor for extracellular cyclophilins. However, the role of cyclophilins and CD147 in leukocyte trafficking and recruitment under physiological or pathological conditions is not known. We now propose to investigate the contribution of these proteins to autoimmune arthritis using collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis. The following Specific Aims will be pursued: Aim 1: To reduce inflammation in CIA using modified cyclosporine A intervention; Aim 2: To characterize the chemotactic contribution of extracellular cyclophilins to CIA pathogenesis; Aim 3: To evaluate the contribution of the chemotactic versus the MMP-inducing activity of CD147 to CIA pathogenesis. Results of these studies will provide information on the mechanisms that regulate leukocyte trafficking in rheumatoid arthritis and will help identify and test therapeutic reagents that, by antagonizing leukocyte extravasation and reducing MMP production, could prevent inflammatory response and may also protect joint tissues from autoimmune inflammatory attacks even when the immune response has already been generated.