CHARACTERIZATION OF E-SELECTIN-DEFICIENT MICE - DEMONSTRATION OF OVERLAPPING FUNCTION OF THE ENDOTHELIAL SELECTINS

The initial rolling interaction of leukocytes with the blood vessel wa ll during leukocyte trafficking has been postulated to rely on members of the selectin family of adhesion molecules. Two selectins, E-select in and P-selectin, have been identified that are expressed on activate d endothelial cells. Mice deficient in E-selectin expression have been produced in order to examine the role of this selectin in leukocyte t rafficking. Mice homozygous for an E-selectin null mutation were viabl e and exhibited no obvious developmental alterations. E-selectin-defic ient mice displayed no significant change in the trafficking of neutro phils in several models of inflammation. However, blocking both endoth elial selectins by treatment of the E-selectin-deficient animals with an anti-murine P-selectin antibody, 5H1, significantly inhibited neutr ophil emigration in two distinct models of inflammation. While neutrop hil accumulation at early times during thioglycollate-induced peritoni tis was dependent on P-selectin, neutrophil accumulation at later time points was blocked by 5H1 only in E-selectin-deficient mice but not i n wild-type mice. Similarly, edema as well as leukocyte accumulation i n a model of delayed-type hypersensitivity in the skin was almost comp letely prevented by blockade of P-selectin function with 5H1 in the E- selectin-deficient mice while the same treatment had no effect in wild -type mice. These data demonstrate that the majority of neutrophil mig ration in both models requires an endothelial selectin but that E-sele ctin and P-selectin are functionally redundant. These data have import ant implications in the use of selectin antagonists in the treatment o f inflammatory disease.