Clocking leukocytes reveal dynamics of integrin braking.

In this issue, Willenbrock et al. (1) address how leukocytes achieve deceleration during rolling and arrest on endothelium in the vasculature near tissue sites of inflammatory insult. While cell capture from the blood stream and rolling is largely the functional domain of selectin adhesion receptors that are constitutively expressed on leukocytes and rapidly deployed on endothelium to bind glycosylated ligands, they are not sufficient to decelerate leukocytes. This is the function of integrins, which are transmembrane heterodimers consisting of a large head on two legs that extend during cell activation to mediate ligand binding (2). Most of the heterodimer is expressed extracellularly, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains where they dynamically assemble with cytoskeletal and signaling complexes. Thus, ligand binding via integrins facilitates cell arrest in the stiff shear force of blood flow and serves to bridge the extracellular milieu to the intracellular cytoskeleton—a critical step for initiating transendothelial migration (3). Two decades have elapsed since natural mutations were discovered in the genes coding for integrin and selectin receptors that cause human leukocyte adhesion deficiency disease, LAD-I and LAD-II, respectively (4). Intense study of the relationship between structure and function has revealed that integrins