IMPORTANCE OF E-SELECTIN FOR FIRM LEUKOCYTE ADHESION IN-VIVO

Leukocyte adhesion under flow is preferentially mediated by the select ins. In this study we used intravital microscopy to investigate whethe r E-selectin may promote firm leukocyte adhesion in vivo, E-Selectin i s expressed by endothelial cells activated with tumor necrosis factor- ct (TNF-ct) and causes slow leukocyte rolling. Microinjection of formy l-methionyl-leucyl-phenylalanine (fMLP) or macrophage inflammatory pro tein-2 (MIP-2) next to a venule of the TNF-alpha-treated mouse cremast er muscle significantly increased the number of adherent leukocytes. I n gene-targeted mice homozygous for a null mutation in the E-selectin gene or in wild-type mice treated with an E-selectin monoclonal antibo dy (mAb), this response was significantly attenuated (by >80%). No suc h defect was seen in intercellular adhesion molecule-1 (ICAM-1)-defici ent mice. E-Selectin-null mice showed more rapid leukocyte rolling tha n wild-type or ICAM-1-deficient mice, resulting in significantly short ened leukocyte transit times through venules. Topical application of f MLP onto the whole cremaster muscle generated the same number of adher ent leukocytes in wild-type and E-selectin-deficient mice. We conclude that slow leukocyte rolling through E-selectin results in long transi t times, which are essential for efficient leukocyte adhesion in respo nse to a local chemotactic stimulus.