Severely reduced neutrophil adhesion and impaired host defense against fecal and commensal bacteria in CD18-/- P-selectin-/- double null mice

Leukocyte recruitment to sites of inflammation requires the functions of selectors and integrins. P-selector null (CD62P- /-) mice show a mild and CD18 null (CD18 /-) mice a more severe neutrophil recruitment defect in some inflammatory models. To investigate the possible cooperative interactions between CD18 integrins and P-selector in mediating neutrophil recruitment, we generated CD18 - /- CD62P - /- double null mice. CD18 /- CD62P /- mice were apparently normal at weaning and fertile but later failed to gain weight, showed increased susceptibility to infection by fecal and commensal bacteria, and survived only 5-6 months. Some CD18-/-CD62P-/- mice showed severe spontaneous skin lesions; most showed neutrophil infiltration in the lungs and liver, and positive bacterial cultures from internal organs. The number and velocity of rolling leukocytes in tumor necrosis factor a treated venules of CD18-/-CD62P-/- mice was similar to those in wild-type mice, but neutrophil adhesion was severely reduced. Only 25% of adhered leukocytes were neutrophils in CD18-/-CD62P-/mice vs. >90% in wild-type, CD62P-/-, and CD18-/- single mutants. Our data show that removing both P-selectin and CD18 integrins from mice leads to severe neutrophil recruitment defects and spontaneous pathology.