Leukocyte recruitment is a hallmark of inflammatory diseases including vascular inflammation such as arthritis, vasculitis, and atherosclerosis. The proposed research addresses the possible cooperative roles of selectins and integrins in mediating efficient leukocyte recruitment to sites of inflammation. The hypothesis is that mice lacking CD18 integrins and E-selectin (CD18-/CD62E-/-) or CD18 integrins and P-selectin (CD18-/-CD62P-/-) will show a severe phenotype due to the inability to recruit leukocytes to sites of inflammation. To test this hypothesis, mice deficient in CD18 integrins and E- selectin or P-selectin will be generated by cross-breeding the single mutants. An alternative approach to produce adult CD18-/- CD62E-/and CD18-/-CD62P-/- mice is by transplanting CD18-/- bone marrow into lethally irradiated CD62E-/- and CD62P-/- mice. The phenotype of mice lacking CD18 integrins and E-selectin or P- selectin will be investigated by histopathology, leukocyte recruitment assays, intravital microscopy, and bone marrow analysis. The efficiency of leukocyte recruitment in these mice will be studied in a TNF-alpha-induced model of inflammation of the cremaster muscle. The efficiency of leukocyte recruitment in mice lacking CD18 integrins and E-selectin or P-selectin will further be studied using a thioglycollate-induced peritonitis model of inflammation. These studies will provide a better understanding of the cooperative roles of selectins and integrins in mediating efficient leukocyte recruitment to sites of inflammation. It is desired to elucidate aspects of the leukocyte adhesion cascade efficiently mediated by the cooperative functions of selectins and integrins that cannot be compensated for by other molecules or adhesion pathways. These adhesion molecules would then be attractive targets for therapeutic intervention when controlling leukocyte recruitment is necessary.
