Abstract
Arrest of rapidly flowing neutrophils in venules relies on capturing through selectins and chemokine-induced integrin activation. Despite a long-established concept, we show here that gene inactivation of activating paired immunoglobulin-like receptor (PILR)-β1 nearly halved the efficiency of neutrophil arrest in venules of the mouse cremaster muscle. We found that this receptor binds to CD99, an interaction which relies on flow-induced shear forces and boosts chemokine-induced β2-integrin-activation, leading to neutrophil attachment to endothelium. Upon arrest, binding of PILR-β1 to CD99 ceases, shifting the signaling balance towards inhibitory PILR-α. This enables integrin deactivation and supports cell migration. Thus, flow-driven shear forces guide sequential signaling of first activating PILR-β1 followed by inhibitory PILR-α to prompt neutrophil arrest and then transmigration. This doubles the efficiency of selectin-chemokine driven neutrophil arrest by PILR-β1 and then supports transition to migration by PILR-α.