Therapeutic Targeting of Pattern Recognition Scavenger Receptor for Treatment of Rheumatoid Arthritis
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. The prevalence of RA is approximately one percent of the general population, with a three-fold female preponderance. Its relevance to the Department of Veterans Affairs (VA) health system has grown with the increase in women Veterans. Men with RA, a disease demographic common in the VA, seem to experience a more severe disease arthritis course than do women with RA and more commonly have extra-articular manifestations, which are known to contribute to worse outcomes. Veterans and people in the general community with post-traumatic stress disorder are at higher risk for having arthritis, including RA. RA is characterized by inflammatory synovitis, joint destruction, muscle atrophy, and bone destruction. In addition to a greater comorbidity burden with physical illnesses, patients also suffer from psychological and social context of RA pain. The pathogenesis of RA is often associated with activation of immune cells and osteoclasts that cascade into a vicious cycle of inflammation and bone erosion. However, the fundamental mechanisms underlying how excessive inflammation and bone erosion develop and are sustained chronically in RA remain largely unknown. In this application, we will investigate a previously unreported cellular network involving an innate pattern recognition receptor called SRA, which is responsible for dysregulated inflammation and bone injury in autoimmune arthritis. While a pathogenic role of SRA in cardiovascular diseases (e.g., atherosclerosis) has been previously documented, little is known about the function of this molecule in autoimmune arthritis, such as RA. We recently made an unexpected discovery that lack of SRA in a widely studied mouse model of RA conferred protection against induction of autoimmune arthritis. This enhanced resistance to arthritic development was associated with marked attenuation of tissue inflammation and bone erosion in the joints. Our data strongly suggest that SRA represents a previously unrecognized key molecule capable of controlling or amplifying activation of inflammatory cells and osteoclasts. Using clinically relevant mouse models and comprehensive molecular/cellular/immunological approaches, we will critically examine and validate the crucial role of SRA and SRA-expressing immune cells in pathogenic processes of RA. We will dissect the SRA-dependent pathways that are required for two highly interactive pathogenic immune cell populations to impact on abnormal inflammation and osteoclastogenesis. In addition, we will perform proof-of-concept studies to test our newly developed immunological drugs that can block SRA activity for therapeutic treatment of RA in clinically relevant models. Successful completion of the proposed research will advance our understanding of the complexity of pro-inflammatory and pro-osteoclastogenic pathways that are directly involved in the pathogenesis of RA. Elucidation of SRA action in driving a self-perpetuating pathogenic loop and preclinical evaluation of biological anti-SRA agents will facilitate clinical development of novel SRA-targeting approaches for therapeutic testing in RA patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910538
Entities
People
- Xiang-Yang Wang
Organizations
- United States Army
- Virginia Commonwealth University