TRANSIT-TIME OF LEUKOCYTES ROLLING THROUGH VENULES CONTROLS CYTOKINE-INDUCED INFLAMMATORY CELL RECRUITMENT IN-VIVO

Leukocyte recruitment requires leukocyte rolling, activation, firm adh esion, and transmigration. Injection of the proinflammatory cytokine T NF-alpha induces expression of E-selectin, interleukin-8, and other ad hesion molecules and chemoattractants on the endothelial surface. TNF- alpha-treated CD18 null mouse cremaster muscle venules show increased leukocyte rolling velocity and reduced leukocyte recruitment efficienc y. Leukocyte recruitment in CD18 null but not wild-type mice is signif icantly blocked by an mAb to E-selectin. To understand this overlap be tween adhesion events previously considered separate, we introduce a q uantitative analysis of the efficiency of induction of rolling, conver sion of rolling to adhesion, and of adhesion to transmigration. We fin d that CD18 and E-sdectin cooperate to control the time a leukocyte ne eds to roll through an inflamed area and to convert rolling to firm ad hesion. Leukocyte rolling time, defined as the time it takes for a rol ling leukocyte to pass through a defined length of a vessel segment, e merges as a unifying parameter determining the efficiency of inducing firm adhesion, which is a rate-limiting step controlling leukocyte rec ruitment in inflammation. We conclude that leukocytes integrate chemoa ttractant signals while rolling along the endothelial surface until th ey reach a critical level of activation and become firmly adherent.