Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo.
Leukocyte recruitment requires leukocyte rolling, activation, firm adhesion, and transmigration. Injection of the proinflammatory cytokine TNF-alpha induces expression of E-selectin, interleukin-8, and other adhesion 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 efficiency. Leukocyte recruitment in CD18 null but not wild-type mice is significantly blocked by an mAb to E-selectin. To understand this overlap between adhesion events previously considered separate, we introduce a quantitative analysis of the efficiency of induction of rolling, conversion of rolling to adhesion, and of adhesion to transmigration. We find that CD18 and E-selectin cooperate to control the time a leukocyte needs to roll through an inflamed area and to convert rolling to firm adhesion. Leukocyte rolling time, defined as the time it takes for a rolling leukocyte to pass through a defined length of a vessel segment, emerges as a unifying parameter determining the efficiency of inducing firm adhesion, which is a rate-limiting step controlling leukocyte recruitment in inflammation. We conclude that leukocytes integrate chemoattractant signals while rolling along the endothelial surface until they reach a critical level of activation and become firmly adherent.
Jung
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U
Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Norman
K E
KE
Scharffetter-Kochanek
K
K
Beaudet
A L
AL
Ley
K
K
D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology*; D019040:E-Selectin / Q000378:metabolism*; D006439:Hemodynamics; D007249:Inflammation / Q000209:etiology; D007958:Leukocyte Count; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D013997:Time Factors; D014699:Venules / Q000502:physiology*
D018821:CD18 Antigens; D016207:Cytokines; D019040:E-Selectin