Novel chemokine functions in lymphocyte migration through vascular endothelium under shear flow

The recruitment of circulating leuko- cytes at vascular sites in target tissue has been linked to activation of Gi-protein signaling in leu- kocytes by endothelial chemokines. The mecha- nisms by which apical and subendothelial chemo- kines regulate leukocyte adhesion to and migration across endothelial barriers have been elusive. We recently found that endothelial chemokines not only stimulate integrin-mediated arrest on vascular endothelial ligands but also trigger earlier very late antigen (VLA)-4 integrin-mediated capture (tether- ing) of lymphocytes to vascular cell adhesion mol- ecule 1 (VCAM-1)-bearing surfaces by extremely rapid modulation of integrin clustering at adhesive contact zones. This rapid modulation of integrin avidity requires chemokine immobilization in jux- taposition with the VLA-4 ligand VCAM-1. We also observed that endothelial-bound chemokines pro- mote massive lymphocyte transendothelial migra- tion (TEM). It is interesting that chemokine-pro- moted lymphocyte TEM requires continuous expo- sure of lymphocytes but not of the endothelial barrier to fluid shear. It is noteworthy that lympho- cyte stimulation by soluble chemokines did not promote lymphocyte TEM. Our results suggest new roles for apical endothelial chemokines both in triggering lymphocyte capture to the endothelial surface and in driving post-arrest events that pro- mote lymphocyte transmigration across endothe- lial barriers under shear flow. J. Leukoc. Biol. 69: 860-866; 2001.