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

摘要

We extend our previous analyses of mice deficient in selectins by describing the generation and com- parative phenotype of mice lacking one, two, or three selectins after sequential ablation of the murine genes encoding P-, E-, and L-selectins. All mice deficient in selectins are viable and fertile as homozygotes. However, mice missing both P- and E-selectins (PE~-/-), and mice missing all three selectins (ELP~-/-) develop mucocutaneous infections that eventually lead to death. Mice deficient in multiple selectins display varying degrees of leukocytosis, resulting in part from alter- ations in leukocyte rolling and recruitment. PE~-/- mice, ELP~-/- mice, and mice missing both P- and L-selectins (PL~-/-) show drastic reductions in leukocyte rolling and in extravasation of neutrophils in thioglycollate-induced perlto- nitis. In a separate inflammatory model (ragweed-induced peritoneal eosinophilia), we demonstrate P-selectin to be both necessary and sufficient for the recruitment of eosinophils. The phenotype of mice missing both E- and L-selectins (EL~-/-) is less severe than those seen in the other double knockouts. Comparisons among the double knockouts suggest that P-selectin normally cooperates. with both E- and L- selectins. Our results indicate a preeminent role for P-selectin in regulating leukocyte behavior in mice. Data from the ELP~-/- mice indicate, however, that all three selectins are important to leukocyte homeostasis and efficient neutrophil recruitment.