A major component of many inflammatory diseases of the gastrointestinal, respiratory and urinary tract is migration of large numbers of neutrophil PMN across the epithelium and accumulation within a lumen. Examples include inflammatory bowel diseases (IBD), cholangitis, cholecystitis, bronchial pneumonia, bronchitis, pyelonephritis, and cystitis. In these conditions, epithelial injury, disease activity and patient symptoms parallel with PMN infiltration into the mucosa. While many studies suggest that PMN transepithelial migration is dependant on leukocyte ?2 integrin CD11b/CD18 (Mac-1, CR3), the mechanisms that govern CD11b/CD18-mediated PMN transepithelial migration are largely unknown. The fundamental issues, such as: a) what are the epithelial counterreceptor(s) for CD11b/CD18 and b) how do adherent PMN detach following CD11b/CD18-mediated initial adhesion in order to migrate forward, still remain to be addressed. Recently, we have found an epithelial fucosylated glycoprotein that serves as a counterreceptor for CD11b/CD18 in migrating PMN and have produced a monoclonal antibody (clone AF8.1) that reacts with this basolaterally expressed antigen. In addition, we have strong preliminary data suggesting that PMN disengagement from cellular and extracellular ligands is mediated by adhesion-induced proteolytic cleavage of PMN surface CD11b. The overall goals of this project are twofold: to define an epithelial counterreceptor for CD11b/CD18; and to investigate a novel mechanism that regulates PMN detachment after CD11b/CD18-mediated cell adhesion during PMN migration. We will test our hypotheses through three specific aims: 1) To identify the AF8.1 antigen that serves as a CD11b/CD18 counterreceptor during the initial events in PMN transmigration; 2) To characterize the CD11b extracellular domain cleavage mechanism and define its role in PMN transepithelial migration, and 3) To determine the role of three structurally related leukocyte serprocidins in CD11b shedding. The studies from this proposal will yield novel insights into understanding the molecular basis of PMN transmigration. Information gained from such studies will also be useful for designing therapeutic strategies aimed at attenuating leukocyte infiltration involved in pathologic mucosal inflammation. Leukocytes (neutrophil) transmigration across blood vessel endothelial lining, interstitial tissues and mucosal surfaces plays a central role in host defense, innate immunity, and many inflammatory diseases. The overall goal of this proposal is to further investigate the molecular mechanisms involved in leukocyte transmigration. Studies from this proposal will reveal new insights that are useful for designing new therapeutic strategies / agents aimed at controlling leukocyte migration and attenuating pathologic inflammation. ? ? ? ?
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