From rolling to arrest on blood vessels: leukocyte tap dancing on endothelial integrin ligands and chemokines at sub-second contacts

In order to extravasate the bloodstream at specific sites of inflammation or antigen presentation, circulating leukocytes must rapidly translate specific adhesive and stimulatory signals into firm adhesion. Leukocyte arrest is nearly exclusively mediated by integrin receptors. Recent in vitro and in vivo evidence suggests that specialized integrins support reversible tethers that slow down selectin-initiated rolling of leukocytes prior to their arrest. In situ activation of integrin avidity by ligand and chemokine signaling can take place within fractions of seconds, resulting either in augmented reversible adhesions or immediate arrest on the vascular endothelium. The ability of leukocyte integrins to rapidly respond to these in situ avidity modulators appears to depend on preformed affinity and clustering states, which are internally regulated by cytoskeletal constraints on integrin conformation and mobility. We discuss potential regulatory mechanisms by which a given set of chemokine receptors and integrins may interact to rapidly generate high avidity, shear-resistant integrin-mediated leukocyte arrest on vascular endothelium.