L-SELECTIN AND VERY LATE ANTIGEN-4 INTEGRIN PROMOTE EOSINOPHIL ROLLING AT PHYSIOLOGICAL SHEAR RATES IN-VIVO

Adherence of eosinophils to vascular endothelium and their accumulatio n at sites of allergen challenge are hallmarks of allergic inflammatio n. However, the molecular mechanisms mediating eosinophil adhesion und er conditions of blood flow are not well understood. The present studi es were performed to identify the receptors on human eosinophils invol ved in initiating adhesion to activated endothelium at physiologic she ar rates in vivo. We have compared the relative contribution of L-sele ctin, VLA-4 (CD49d), and CD18 integrins in mediating eosinophil adhesi on to microvascular endothelial cells in the rabbit mesentery by using intravital video microscopy. Eosinophils were found to roll in venule s, but not arterioles, and this rolling could be stimulated by activat ion of endothelium with IL-1. In contrast to neutrophil rolling, which is predominantly L-selectin-dependent, eosinophil rolling was mediate d by L-selectin, and also VLA-4. mAbs to L-selectin and VLA-4 alpha, b ut not CD18, significantly inhibited eosinophil rolling in vivo. The i nhibition of VLA-4-mediated eosinophil rolling was not caused by modul ation of eosinophil L-selectin or CD18 expression. This inhibition als o was not caused by nonspecific inhibitory effect of the Abs studied, because the anti-VLA-4 mAbs inhibited eosinophil (VLA-4(+)) but not ne utrophil (VLA-4(-)) rolling in the mesenteric venules. These results d emonstrate that early events of eosinophil adhesion, i.e., rolling, ar e mediated by multiple adhesion receptors, including L-selectin and VL A-LF, at physiologic shear rates in vivo.