Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy of unknown etiology. In patients with RA there are increased numbers of monocytes, which exists as multiple populations circulating in peripheral blood but the requirement and/or necessity of an individual population in RA remains to be determined. In the joint, these monocytes then differentiate into macrophages leading to an elevation in number, which is associated with articular destruction in RA patients In RA, macrophages are highly activated, express elevated levels of toll-like receptor 3 and 4, and contribute directly and indirectly to synovial inflammation and destruction of cartilage and bone through the production of degradative enzymes, cytokines, and chemokines. Of note, macrophages are the central producers of IL-1, IL-6, and TNF, three essential pro-inflammatory cytokines that contribute to RA pathogenesis. Due to the success of the biologic therapy, these data indicate macrophages may be considered upstream mediators of RA. Inhibitors to IL-1 and TNFα reduce synovial inflammation, bone destruction, and macrophage infiltration in RA patients. Further, macrophage number is the only accurate biomarker for determination of successful therapy for RA. Despite the fact that synovial macrophages were discovered more that half-century ago surprisingly, very little is known about them. Thus, the data anticipated from these studies will confirm that the current dogma concerning monocytes may no be applicable to RA (Aim 1). Further, we will identify the origin and genetic program that exists in the various populations of synovial macrophages during steady state and sterile inflammation (Aim 2). Moreover, we will uncover the mechanism responsible for altering macrophage polarization that results in the resolution of inflammatory arthritis (Aim 3). Taken together, these data will delineate novel targets for RA that is specific to the synovial macrophages, which are one of the central cells that contribute to the pathogenesis of RA. We believe that the investigative team assembled for this grant will lead to novel and transformative breakthroughs in RA research and ultimately new therapeutics or targets for RA patients.
|Effective start/end date||7/1/14 → 6/30/16|
- Rheumatology Research Foundation (Agmt. Signed 5/6/14)
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