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

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Abstract
CD18-deficient mice (CD18–/– mice) have a severe leukocyte recruitment defect 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 neutrophil infiltration, depending on the model. CD18–/–CD62E–/–, but not CD18–/–CD62P–/–, mice generated by crossbreeding failed to thrive, reaching a maximum body weight of 10–15 grams. To explore the mechanisms underlying reduced viability, we investigated lethally irradiated CD62E–/– mice that were reconstituted with CD18–/– bone marrow. These mice, but not single-mutant controls, showed tenfold-increased rolling velocities in a TNF-α–induced model of inflammation. Leukocyte adhesion efficiency in CD18–/–CD62E–/– mice was reduced by 95%, and hematopoiesis was drastically altered, 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 integrins is necessary for neutrophil recruitment and that alternative adhesion pathways cannot compensate for the loss of these molecules.