Mice lacking E-selectin show normal numbers of rolling leukocytes but reduced leukocyte stable arrest on cytokine-activated microvascular endothelium

Objective: Previous work indicated that E-selectin mediates transient inter actions between leukocytes and cytokine-activated endothelium in vitro. Her e we examine the role of E-selectin in blood leukocyte interactions with mi crovascular endothelium in vivo. Methods: E-selectin-deficient (E-/-) mice were produced by gene targeting. The effect of this null mutation on leukocyte-endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local adm inistration of the proinflammatory cytokine tumor necrosis factor alpha (TN F alpha) in dermal microvessels with low blood flow (dorsal skin-fold chamb ers, intact ear skin), and after endotoxin activation in exteriorized mesen teric microvessels ai-ah higher blood flow. Results: E-/- mice were viable, fertile with normal circulating leukocyte a nd platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E-/- mice without inflammato ry stimulation. After local administration of TNF alpha, rolling increased modestly and equivalently in both genotypes. The main effect of TNF alpha w as a dramatic increase in leukocyte stable adhesion and, unlike rolling, th is manifestation of endothelial activation was significantly reduced in E-/ - animals. This reflected fewer dermal microvessels supporting higher adhes ion densities ill E-/- mice, and a similar trend was observed in mesenteric microvessels. Conclusions: E-selectin plays a previously unappreciated role in facilitati ng and/or mediating stable adhesion of leukocytes to inflamed microvascular endothelium.