The role of fas signaling in rheumatoid arthritis

描述(申请人提供)：RA是一种慢性自身免疫性疾病，表现为持续的滑膜炎症、细胞浸润和促炎细胞因子的产生，并导致进行性软骨和骨破坏。虽然RA相关自身免疫表型的机制尚未完全阐明，但细胞凋亡不足是疾病发病机制中的一个基本因素。外源性细胞凋亡途径的中介分子包括参与启动细胞凋亡信号的死亡受体Fas，以及参与细胞凋亡信号传递的FADD和caspase-8。淋巴细胞特异性的Fas、FADD或caspase-8的缺失揭示了这些信号介质在增殖中的非凋亡作用。特别值得注意的是，B细胞特异性缺失FADD和caspase-8会削弱Toll样受体(TLR)诱导的增殖，从而可能影响NFKB和MAPK信号通路的下游激活。虽然淋巴细胞是启动类风湿性关节炎所必需的，但巨噬细胞对这种衰弱疾病的持续至关重要。这些细胞高度激活，表达增加的TLR3和4水平，通过产生降解酶、细胞因子和趋化因子来促进滑膜炎症、软骨和骨破坏，并且与B细胞不同，它们不增殖。然而，Fas及其信号介质在髓系细胞中的特异性缺失尚未得到研究。对老年CreLysMFasflx/FLOX小鼠的初步评估表明，这种信号媒介的选择性缺失通过增加外周血中常驻单核细胞的水平，以及增加总巨噬细胞和炎性脾巨噬细胞的数量和激活水平，破坏了外周髓系细胞的动态平衡。基于这些数据，我们认为Fas及其下游信号伙伴FADD和caspase-8是炎症的抑制因子。在这项研究中，我们将确定髓系细胞特异性缺失Fas及其信号伙伴对髓系细胞发育以及炎性关节炎的发展和严重程度的影响。此外，我们还建议确定巨噬细胞中需要Fas、FADD和caspase-8信号的非凋亡途径。类风湿性关节炎的治疗一直以纠正有缺陷的Fas信号为目标，尽管如果Fas是非凋亡细胞功能所必需的，这可能会产生有害的结果，如B细胞特异性缺失Fas信号介质所示。因此，本项目旨在阐明与Fas启动的外在细胞凋亡途径经典相关的信号介导物在髓系细胞中的新的非凋亡作用。综上所述，该建议采用细胞特异性的方法来确定Fas、FADD和caspase-8在巨噬细胞功能、炎性关节炎的易感性以及最重要的TLR信号中的非凋亡性参与，到目前为止还没有被研究过。 公共卫生相关性：细胞凋亡缺陷与类风湿性关节炎的发病机制以及滑膜中炎性巨噬细胞的持续存在有关。类风湿性关节炎的治疗一直以纠正有缺陷的Fas信号为目标，尽管如果Fas是非凋亡细胞功能所必需的，这可能会产生有害的结果，如B细胞特异性缺失Fas信号介质所示。因此，本项目旨在阐明与Fas启动的外在细胞凋亡途径经典相关的信号介导物在髓系细胞中的新的非凋亡作用。

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.