The Role of Beta-Arrestins 1 and 2 in Rheumatoid Arthritis

促炎细胞因子和趋化因子在类风湿关节炎（RA）中起着关键作用。最近的研究 已经阐述了Toll样受体（TLR）在RA的发展和进展中的作用。一个重要 各种TLR在关节炎动物模型中的作用已经得到证实。TLR 4和内源性TLR 4 配体如透明质酸和热休克蛋白（HSP）22在RA的滑膜组织中高度表达， 与健康供体相比，患者进一步暗示类风湿性关节炎发病机制中的TLR。然而，信号 调节RA中内源性TLR 4配体诱导的TLR活化的途径尚未完全了解。 最近的研究表明，接头蛋白B和TRAF 6相关的抑制蛋白1和2， NF B1 p105负调控TLR信号传导。我们的数据首次证明â-arrestin 2 敲除（KO）小鼠在胶原抗体诱导的关节炎（CAIA）模型中表现出更严重的关节炎 与野生型（WT）小鼠相比。此外，我们还观察到，抑制蛋白1和抑制蛋白2的表达增加， 在胶原诱导的关节炎（CIA）小鼠的脾细胞和成纤维细胞样滑膜细胞（FLS）中， 对照组小鼠。还证明LPS-和内源性TLR 4配体低分子量 透明质酸（LMW-HA）诱导的TNF-α，IL-6和IL-10的产生在脾细胞中增加， 与WT小鼠相比，抑制蛋白2 KO小鼠。这些发现使我们提出了一个假设，即上调 抑制蛋白1和2的表达抑制了胶原诱导的关节炎的炎症， 调节炎症细胞反应。具体的目的是研究<$-arrestin 1和2的作用， 胶原诱导性关节炎炎症反应的负调节因子。抑制蛋白1和2的表达 脾巨噬细胞，CD 4+和CD 8 + T淋巴细胞，B淋巴细胞，树突状细胞（DC）， 在小鼠CIA模型中，多形核白细胞（PMN）和FLS与疾病严重程度的相关性将 接受检查。一旦鉴定出表现出抑制蛋白表达改变的特异性免疫细胞， 将使用慢病毒表达来检测抑制蛋白1和2表达对这些细胞活化的作用 系统过表达抑制蛋白或用RNAi敲低抑制蛋白。理解依赖于逮捕的 调节促炎和抗炎基因表达的信号通路将为研究炎症反应提供新的见解。 RA的发病机制，创新的有针对性的干预措施可以演变。

Pro-inflammatory cytokines and chemokines play critical roles in rheumatoid arthritis (RA). Recent studies have addressed the role of toll-like receptors (TLR)s in the development and progression of RA. An important role of various TLRs in the animal model of arthritis has been demonstrated. TLR4 and endogenous TLR4 ligands such as hyaluronan and heat shock protein (HSP)22 are highly expressed in synovial tissue from RA patients compared with healthy donors further implicating TLRs in RA pathogenesis. However the signaling pathways that regulate endogenous TLR4 ligands-induced TLR activation in RA are not fully understood. Recent studies demonstrated that adaptor proteins ¿-arrestin 1 and 2 associating with TRAF6, I¿B¿, and NF¿B1p105 negatively regulate TLR signaling. Our data demonstrated for the first time that ¿-arrestin 2 knockout (KO) mice exhibited more severe arthritis in the collagen antibody-induced arthritis (CAIA) model compared to wild type (WT) mice. Furthermore, we observed that ¿-arrestin 1 and 2 expression are increased in splenocytes and fibroblast-like synoviocytes (FLS) in the collagen-induced arthritis (CIA) mice compared to the control mice. It was also demonstrated that LPS- and the endogenous TLR4 ligand low molecular weight hyaluronan (LMW-HA)- induced TNF¿, IL-6 and IL-10 production were augmented in splenocytes from ¿- arrestin 2 KO mice compared to WT mice. These findings led us to propose the hypothesis that up-regulation of ¿-arrestin 1 and 2 expression suppresses inflammation in collagen-induced arthritis by negative regulation of inflammatory cell responses. The specific aim is to investigate the role of ¿-arrestin 1 and 2 as negative regulators of the inflammatory response in collagen-induced arthritis. ¿-arrestin 1 and 2 expression in splenic macrophages, CD4+ and CD8+ T lymphocytes, B lymphocytes, dendritic cells (DC)s, polymorphonuclear leukocyte (PMN)s and FLS correlation to the disease severity in the mouse CIA model will be examined. Once the specific immune cells that exhibit altered expression of ¿-arrestins are identified, the role of ¿-arrestin 1 and 2 expression on activation of these cells will be examined using the lentiviral expression system to overexpress ¿-arrestins or knock down ¿-arrestins with RNAi. Understanding ¿-arrestins-dependent signaling pathways that regulate pro- and anti-inflammatory gene expression will provide novel insights into the pathogenesis of RA from which innovative targeted interventions can evolve.