Macrophage Infiltration of Renal Tissue via beta-3 Integrins and Agrin

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DESCRIPTION (provided by applicant): Glomerulonephritis is most commonly an autoimmune-induced inflammatory event wherein infiltration of the kidney by macrophages results in loss of renal function due to fibrosis. The long-term goal of our laboratory is to identify the molecular switches that govern macrophage adhesion and thus regulate the inflammatory response. We previously identified tyrosine phosphorylation of 23 integrin adhesion receptors as one such switch and have demonstrated that 23 phosphorylation is necessary for macrophage adhesion to some ligands. Blockade of 23 phosphorylation results in loss of adhesion due to a failure of the actin cytoskeleton to organize into stress fibers. In this application we present evidence that this unique mechanism is required for macrophage entry into renal tissues. We hypothesize that macrophage passage through renal basement membrane is mediated by an interaction between the proteoglycan agrin and phosphorylated 23 integrins. In this application we will assess the role of 23 integrins and their phosphorylation in migration to renal tissues during experimental glomerulonephritis. We will determine whether agrin in renal basement membrane regulates macrophage infiltration by in vitro transmigration studies. We will characterize the production of macrophage podosomal adhesions and pseudopods that are required for migration into three-dimensional tissues by TIRF microscopy of living macrophages. We will biochemically determine the signaling from phosphorylated 23 that controls actin cytoskeletal reorganization in the macrophage pseudopod and podosome. Identification of mechanisms used during organ-specific macrophage immune trafficking can provide novel targets for therapeutic intervention and complement global immune-suppressive therapies. PUBLIC HEALTH RELEVANCE: r laboratory has identified a new mechanism of white blood cell adhesion to tissues. This research proposal will determine whether a particular adhesion molecule called 23 integrin, found on a subset of white blood cells, contributes to glomerulonephritis (inflammation of the kidneys). Understanding the mechanism of glomerulonephritis can provide new targets for drugs to reduce the progression of this disease.