A non-cell autonomous requirement for neutrophil BLT1 in inflammatory arthritis

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DESCRIPTION (provided by applicant): Rheumatoid arthritis is a chronic, debilitating disease characterized by accumulation of leukocytes within the joints, resulting in significant pain, destruction, and loss of function. Through adoptive cell transfer studies, we have found that the leukotriene B4 (LTB4) receptor BLT1 upon neutrophils is an absolute requirement for disease in a mouse model of inflammatory arthritis. However, the primary pathogenic role of BLT1- expressing neutrophils is to recruit BLT1-deficient neutrophils into the joint, revealing a novel non-cell autonomous function for the BLT1 chemoattractant receptor that is biologically relevant in the development of inflammatory arthritis. We will study two potential mechanisms by which this process of leukocyte recruitment into the joint may occur. First, we hypothesize that BLT1 is necessary for arthritogenic antibody localization in the joints. We will investigate these potential mechanisms using specialized histological and radiologic techniques to visualize autoantibody deposition. Alternatively, we have previously found that BLT1 is needed for efficient leukocyte transendothelial migration, so we hypothesize that transmigrating BLT1-expressing neutrophils may alter cellular and extracellular matrix barriers, allowing BLT1-deficient neutrophils to transmigrate out of the circulation towards sites of inflammation. We will test this second hypothesis through multiple in vitro and in vivo assays of transendothelial migration. In addition to testing these two mechanism-based hypotheses, we will utilize genomic, proteomic, and metabolomic technologies to determine whether specific BLT1 activation of neutrophils results in the unique expression of factors that enable to them to recruit other cell populations into the joint in inflammatory arthritis. These studies will enable us to understand the role of BLT1 in the pathogenesis of joint-specific inflammation as well as elucidate previously undescribed effects of BLT1 upon leukocyte migration out of the circulation towards sites of inflammation. Rheumatoid arthritis is a chronic, debilitating disease affecting 1% of the world's population, characterized by the accumulation of inflammatory cells within the joints that results in significant pain, destruction, and loss of function. The goal of our research is to understand the specific molecular signals that attract these inflammatory cells into the joint, with the goal of targeting these signals as therapies in rheumatoid arthritis.