Multiple, targeted deficiencies in selectins reveal a predominant role forP-selectin in leukocyte recruitment

We extend our previous analyses of mice deficient in selectins by describin g the generation and comparative phenotype of mice lacking one, two, or thr ee selectins after sequential ablation of the murine genes encoding P-, E-, add L-selectins. All mice deficient in selectins are viable and fertile as homozygotes. However, mice missing both P- and E-selectins (PE-/-), and mi ce missing all three selectins (ELP-/-) develop mucocutaneous infections th at eventually lead to death. Mice deficient in multiple selectins display v arying degrees of leukocytosis, resulting in part from alterations in leuko cyte rolling and recruitment. PE-/- mice, ELP-/- mice,and mice missing both P- and L-selectins (PL-/-) show drastic reductions in leukocyte rolling an d in extravasation of neutrophils in thioglycollate-induced peritonitis, In a separate inflammatory model (ragweed-induced peritoneal eosinophilia), w e demonstrate P-selectin to be both necessary and sufficient for the recrui tment of eosinophils, The phenotype of mice missing both E- and L-selectins (EL-/-) is less severe than those seen in the other double knockouts. Comp arisons among the double knockouts suggest that P-selectin normally coopera tes with both E- and L-selectins, Our results indicate a preeminent role fo r P-selectin in regulating leukocyte behavior in mice. Data from the ELP-/- mice indicate, however, that all three selectins are important to leukocyt e homeostasis and efficient neutrophil recruitment.