Chemokine signaling to lymphocyte integrins under shear flow.

The arrest of lymphocytes at target vascular sites depends on the rapid activation of their integrins by specialized endothelial chemokines. For over a decade, the mechanisms by which these chemokines trigger initial integrin-mediated adhesiveness and subsequent adhesion strengthening and crawling over endothelial surfaces have been dissected in vitro using flow chamber setups. These studies revealed that lymph node chemokines and subsets of inflammatory chemokines, collectively termed "arrest chemokines," can trigger the fastest measurable inside-out integrin activation events. Recent studies indicate that shear forces applied on lymphocytes are instrumental in these rapid activation processes. Different GTPases have been implicated in these activation processes. As these enzymes contribute to successive integrin activation and redistribution processes in both early and prolonged contacts there is a growing need to dissect in vitro and validate in vivo specific signaling routes involved in early and late integrin activation events controlling lymphocyte arrest and their subsequent crawling to sites of diapedesis. In this article, we present an overview of both early and recent shear-flow studies of integrin activation in lymphocytes and discuss future perspectives of integrin activation research in vitro and in vivo.