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

Beta-Arrestins 1 和 2 在类风湿关节炎中的作用

• 批准号: 7911699
• 负责人: Hongkuan Fan
• 金额: $ 7.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911699
• 关键词: Adaptor Signaling Protein; Address; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arrestin Beta 1; Arrestins; Arthritis; Autoimmune Diseases; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cartilage; Cells; Chronic; Clinical Trials; Collagen; Collagen Arthritis; DBA/1J Mouse; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Endotoxins; Exhibits; Experimental Arthritis; Fibroblasts; Gene Expression; Goals; Heat shock proteins; Human; Hyaluronan; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Innovative Therapy; Interleukin-1; Interleukin-10; Interleukin-6; Intervention; Joints; Knock-out; Knockout Mice; Knowledge; Ligands; Lipopolysaccharides; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular Weight; Mus; NF-kappa B; Pathogenesis; Patients; Play; Production; RNA Interference; Receptor Activation; Receptor Signaling; Regulation; Rheumatoid Arthritis; Role; Severity of illness; Signal Pathway; Signal Transduction; Specificity; Splenocyte; Stimulus; System; TLR4 gene; TNF Receptor-Associated Factors; TRAF6 gene; Time; Tissues; Toll-like receptors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Wild Type Mouse; arrestin 1; arrestin 2; chemokine; clinical practice; cytokine; healthy volunteer; inhibitor/antagonist; innovation; insight; joint destruction; knock-down; macrophage; neutrophil; novel; novel strategies; overexpression; public health relevance; research study; response

DESCRIPTION (provided by applicant): 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 2-arrestin 1 and 2 associating with TRAF6, I:B1, and NF:B1p105 negatively regulate TLR signaling. Our data demonstrated for the first time that 2-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 2-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 TNF1, IL-6 and IL-10 production were augmented in splenocytes from 2- arrestin 2 KO mice compared to WT mice. These findings led us to propose the hypothesis that up-regulation of 2-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 2-arrestin 1 and 2 as negative regulators of the inflammatory response in collagen-induced arthritis. 2-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 2-arrestins are identified, the role of 2-arrestin 1 and 2 expression on activation of these cells will be examined using the lentiviral expression system to overexpress 2-arrestins or knock down 2-arrestins with RNAi. Understanding 2-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. PUBLIC HEALTH RELEVANCE: This project investigates the role of 2-arrestin 1 and 2 as negative regulators of inflammatory response in collagen-induced arthritis. Understanding 2-arrestin 1 and 2 expression in correlation to the disease severity and its cellular specificity in the collagen-induced arthritis model in mice and role of 2-arrestin 1 and 2 expression on endogenous Toll-like receptor ligands and other stimuli induced inflammatory response will provide novel insights into the pathogenesis of rheumatoid arthritis from which innovative targeted interventions can evolve.

描述（申请人提供）：促炎细胞因子和趋化因子在类风湿性关节炎（RA）中发挥关键作用。最近的研究已经解决了Toll样受体（TLR）在RA的发展和进展中的作用。各种TLR在关节炎动物模型中的重要作用已得到证实。TLR4和内源性TLR4配体如透明质酸和热休克蛋白（HSP）22在RA患者滑膜组织中的表达高于健康供体，进一步表明TLR参与RA发病机制。然而，调节RA中内源性TLR4配体诱导的TLR活化的信号通路尚未完全了解。最近的研究表明，接头蛋白2-arrestin 1和2与TRAF6，I：B1，NF：B1p105负调控TLR信号。我们的数据首次证明，2-arrestin 2敲除（KO）小鼠在胶原抗体诱导的关节炎（CAIA）模型中表现出比野生型（WT）小鼠更严重的关节炎。此外，我们观察到，2-arrestin 1和2的表达增加的脾细胞和成纤维细胞样滑膜细胞（FLS）的胶原诱导关节炎（CIA）小鼠相比，对照组小鼠。还证明，与WT小鼠相比，LPS和内源性TLR4配体低分子量透明质酸（LMW-HA）诱导的TNF 1、IL-6和IL-10产生在来自2-arrestin 2 KO小鼠的脾细胞中增加。这些发现使我们提出了这样的假设，即2-arrestin 1和2表达的上调通过炎症细胞反应的负调节来抑制胶原诱导的关节炎中的炎症。具体的目的是研究2-arrestin 1和2作为胶原诱导的关节炎中炎症反应的负调节剂的作用。2-将检查小鼠CIA模型中脾巨噬细胞、CD 4+和CD 8 + T淋巴细胞、B淋巴细胞、树突状细胞（DC）、多形核白细胞（PMN）和FLS中抑制蛋白1和2的表达与疾病严重程度的相关性。一旦鉴定出表现出改变的2-抑制蛋白表达的特异性免疫细胞，将使用慢病毒表达系统过表达2-抑制蛋白或用RNAi敲低2-抑制蛋白来检查2-抑制蛋白1和2表达对这些细胞活化的作用。了解调节促炎和抗炎基因表达的2-arrestins依赖性信号通路将为RA的发病机制提供新的见解，从而可以发展创新的靶向干预措施。公共卫生相关性：本项目研究2-arrestin 1和2作为胶原诱导的关节炎中炎症反应的负调节剂的作用。了解2-arrestin 1和2表达与疾病严重程度的相关性及其在小鼠胶原诱导的关节炎模型中的细胞特异性，以及2-arrestin 1和2表达对内源性Toll样受体配体和其他刺激诱导的炎症反应的作用，将为类风湿性关节炎的发病机制提供新的见解，从而可以发展创新的靶向干预措施。