Neutrophil (PMN) migration in the gastrointestinal mucosa is a central component of both host defense and pathophysiologic processes such as inflammatory bowel disease (IBD). While many studies have focused on defining events involved in the regulation of PMN migration at the level of cell adhesion, events that serve to regulate the rate with which PMN migrate through intestinal mucosa during the inflammatory response are poorly understood. Studies from our group have demonstrated important contributions from epithelial and PMN expressed membrane proteins which, upon ligation, initiate signals that have profound effects on the kinetics on PMN transmigration. This proposal will focus on a receptor-ligand pair termed CD47-SIRPalpha and a class of proteins termed protease activated receptors (PARs) that are differentially expressed in the intestinal mucosa and on leukocytes and modulate the rate of PMN transmigration through distinct effects on PMN and epithelial cells. We have observed that exposure of migrating PMN to gut-derived microbial products have profound effects on transmigration that may be linked in part to CD47 mediated signaling and in part to PMN stimulated alterations in epithelial permeability through PARs. Our overall goal is to understand the mechanisms of how CD47, SIRP and PARs regulate PMN transmigration in the gut on a structural and functional basis. To achieve this goal we will perform studies employing in vitro methods in concert with murine models of acute colitis to define the contribution(s) of intestinal epithelial and PMN expressed CD47 and potential crosstalk with TLRs on the rate of PMN transepithelial migration, determine structural elements in SIRPalpha that mediate ligand binding/ protein interactions and investigate the role of PMN-epithelial signaling through PARs in regulating the rate of PMN migration across intestinal epithelium. Understanding basic mechanisms regulating the rate of PMN migration across epithelia may provide clues to the pathophysiology of mucosa! diseases such as IBD and aid in the development of new therapeutic strategies aimed at diminishing enhanced permeability and mucosal injury associated with these conditions.
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