Severe inflammatory defect and reduced viability in CD18 and E-selectin double-mutant mice

CD18-deficient mice (CD18(-/-) mice) have a severe leukocyte recruitment de fect in some organs, and no detectable defect in other models. Mice lacking E-selectin (CD62E(-/-) mice) have either no defect or a mild defect of neu trophil infiltration, depending on the model. CD18(-/-)CD62E(-/-), but not CD18(-/-)CD62P(-/-), mice generated by crossbreeding failed to thrive, reac hing a maximum body weight of 10-15 grams. To explore the mechanisms underl ying reduced viability, we investigated lethally irradiated CD62E(-/-) mice that were reconstituted with CD18(-/-) bone marrow These mice, but not sin gle-mutant controls, showed tenfold-increased rolling velocities in a TNF-a lpha -induced model of inflammation. Leukocyte adhesion efficiency in CD18( -/-)CD62E(-/-) mice was reduced by 95%, and hematopoiesis was drastically a ltered, including severe bone marrow and blood neutrophilia and elevated G- CSF and GM-CSF levels. The greatly reduced viability of CD18(-/-)CD62E(-/-) mice appears to result from an inability to mount an adequate inflammatory response. Our data show that cooperation between E-selectin and CD18 integ rins is necessary for neutrophil recruitment and that alternative adhesion pathways cannot compensate for the loss of these molecules.