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.
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.
|Duffau, Pierre; Menn-Josephy, Hanni; Cuda, Carla M et al. (2015) Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model. Arthritis Rheumatol 67:3146-57|
|Cuda, Carla M; Misharin, Alexander V; Khare, Sonal et al. (2015) Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner. Arthritis Res Ther 17:291|
|Cuda, Carla M; Misharin, Alexander V; Gierut, Angelica K et al. (2014) Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. J Immunol 192:5548-60|
|Huang, Qi-Quan; Birkett, Robert; Koessler, Renee E et al. (2014) Fas signaling in macrophages promotes chronicity in K/BxN serum-induced arthritis. Arthritis Rheumatol 66:68-77|
|Cuda, Carla M; Agrawal, Hemant; Misharin, Alexander V et al. (2012) Requirement of myeloid cell-specific Fas expression for prevention of systemic autoimmunity in mice. Arthritis Rheum 64:808-20|
|Mavers, Melissa; Cuda, Carla M; Misharin, Alexander V et al. (2012) Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis. Arthritis Rheum 64:141-52|