The role of fas signaling in rheumatoid arthritis

fas信号在类风湿性关节炎中的作用

• 批准号: 8003914
• 负责人: Carla M Cuda
• 金额: $ 4.76万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003914
• 关键词: Apoptosis; Apoptotic; Autoimmune Process; B-Lymphocytes; CD95 Antigens; Cartilage; Cell physiology; Cells; Cellular Infiltration; Cessation of life; Data; Development; Disease; Enzymes; Evaluation; Homeostasis; Inflammation; Inflammatory; Lymphocyte; MAPK Signaling Pathway Pathway; Mediator of activation protein; Mus; Myeloid Cells; NF-kappa B; Outcome; Pathogenesis; Pathway interactions; Phenotype; Predisposition; Production; Proliferating; Receptor Signaling; Rheumatoid Arthritis; Role; Severities; Signal Transduction; Synovial Membrane; TLR3 gene; Toll-like receptors; aged; base; bone; caspase-8; chemokine; chronic autoimmune disease; cytokine; interest; macrophage; monocyte; novel; peripheral blood; public health relevance; transmission process

DESCRIPTION (provided by applicant): RA, a chronic autoimmune disease, manifests in persistent synovial inflammation, cellular infiltration, and pro-inflammatory cytokine production, and results in progressive cartilage and bone destruction. While the mechanisms underlying RA-associated autoimmune phenotypes are not fully elucidated, insufficient apoptosis is a fundamental player in disease pathogenesis. Mediators of the extrinsic apoptotic pathway include the death receptor Fas, involved in initiation of the apoptotic signal, and FADD and caspase-8, involved in transmission of the apoptotic signal. Lymphocyte-specific deletion of Fas, FADD, or caspase-8 reveals non-apoptotic roles for these signaling mediators in proliferation. Of particular interest is that B cell-specific deletion of FADD and caspase-8 impairs toll-like receptor (TLR)-induced proliferation with potential consequences on downstream activation of NFKB and MAPK signaling pathways. While lymphocytes are necessary for the initiation of RA, macrophages are crucial for the persistence of this debilitating disease. These cells are highly activated, express increased levels of TLR3 and 4, and contribute to synovial inflammation and cartilage and bone destruction through the production of degradative enzymes, cytokines, and chemokines, and unlike B cells, do not proliferate. However, deficiency of Fas and its signaling mediators specifically in myeloid cells has yet to be examined. Preliminary evaluation of aged CreLysMFasflox/flox mice, which lack Fas specifically in the myeloid cell compartment, shows that selective deletion of this signaling mediator disrupts myeloid cell homeostasis in the periphery by increasing levels of peripheral blood resident monocytes, as well as increasing both the number and activation level of total and inflammatory splenic macrophages. Based on these data, we propose that Fas and its downstream signaling partners, FADD and caspase-8, are suppressors of inflammation. In this study we will determine the impact of myeloid cell-specific deletion of Fas and its signaling partners on myeloid cell development as well as development and severity of inflammatory arthritis. Also, we propose to determine the non-apoptotic pathways that require Fas, FADD and caspase-8 signaling in macrophages. Therapies for rheumatoid arthritis have been aimed at targeting correction of defective Fas-signaling, though this may have detrimental outcomes should Fas be necessary for non-apoptotic cellular functions, as seen in B cell-specific deletion of Fas-signaling mediators. Therefore, this project aims to elucidate novel myeloid cell-specific non-apoptotic roles for signaling mediators classically associated with the Fas-initiated extrinsic apoptotic pathway. In summary, this proposal takes a cell-specific approach to identify the non-apoptotic involvement of Fas, FADD and caspase-8 in macrophage function, susceptibility to the development of inflammatory arthritis, and most importantly in TLR signaling, which to date has never been examined. PUBLIC HEALTH RELEVANCE: Defective apoptosis is associated with rheumatoid arthritis pathogenesis as well as the persistence of inflammatory macrophages in the synovium. Therapies for rheumatoid arthritis have been aimed at targeting correction of defective Fas-signaling, though this may have detrimental outcomes should Fas be necessary for non-apoptotic cellular functions, as seen in B cell-specific deletion of Fas- signaling mediators. Therefore, this project aims to elucidate novel myeloid cell-specific non- apoptotic roles for signaling mediators classically associated with the Fas-initiated extrinsic apoptotic pathway.

描述（由申请人提供）：RA，一种慢性自身免疫性疾病，表现出持续的滑膜炎症，细胞浸润和促炎性细胞因子的产生，并导致进行性软骨和骨骼破坏。虽然与RA相关的自身免疫表型的基础机制尚未完全阐明，但凋亡不足是疾病发病机理的基本作用。外部凋亡途径的介体包括涉及凋亡信号启动的死亡受体FA，以及涉及凋亡信号传播的FADD和CASPASE-8。 FA，FADD或CASPASE-8的淋巴细胞特异性缺失揭示了这些信号传导介质在增殖中的非凋亡作用。特别令人感兴趣的是，FADD和caspase-8的B细胞特异性缺失会损害Toll样受体（TLR）诱导的增殖，并可能对NFKB和MAPK信号途径下游激活产生潜在的后果。尽管淋巴细胞对于启动RA是必需的，但巨噬细胞对于这种使人衰弱的疾病的持续存在至关重要。这些细胞被高度激活，表达TLR3和4的水平升高，并通过产生降解酶，细胞因子和趋化因子和B细胞而导致滑膜炎症，软骨和骨破坏，并且不会增殖。但是，FAS及其信号介质的缺乏在髓样细胞中尚待检查。对髓样细胞室中特别缺乏FA的老年crelysmfasflox/flox小鼠的初步评估表明，该信号介体的选择性缺失通过增加居住的单细胞和散布数量的跨性别的单细胞和变化量增加了外周血液居住的单细胞的水平，从而破坏了周围的髓样细胞稳态。基于这些数据，我们建议FAS及其下游信号伴侣FADD和CASPASE-8是炎症的抑制器。在这项研究中，我们将确定FAS的髓样细胞特异性缺失及其信号伴侣对髓样细胞发育以及炎症性关节炎的发育和严重程度的影响。另外，我们建议确定巨噬细胞中需要FAS，FADD和CASPASE-8信号的非凋亡途径。类风湿关节炎的疗法旨在靶向纠正有缺陷的FAS信号，尽管如果FAS对于非凋亡的细胞功能需要FA，则可能会产生有害的结果，如B细胞特异性缺失的FAS信号介体所见。因此，该项目旨在阐明新型的髓样细胞特异性非凋亡作用，用于与FAS发射的外部凋亡途径经典相关的信号传导介体。总而言之，该提案采用了一种细胞特异性方法来鉴定FAS，FADD和CASPASE-8在巨噬细胞功能中的非凋亡参与，对炎症性关节炎发展的易感性，以及在TLR信号中最重要的，迄今为止从未检查过。 公共卫生相关性：缺陷凋亡与类风湿关节炎发病机理以及滑膜炎性巨噬细胞的持续性有关。类风湿关节炎的疗法旨在靶向纠正缺陷的FAS信号，尽管如果FAS的非凋亡细胞功能需要FAS，则可能会产生有害的结果，如B细胞特异性缺失FAS信号介质的缺失。因此，该项目旨在阐明与FAS引发的外部凋亡途径经典相关的信号传导介体的新型髓样细胞特异性非凋亡作用。