Interstitial leukocyte navigation through a search and run response to gradients

Migrating cells must interpret chemical gradients to guide themselves within tissues. A general premise has been that gradients influence the direction of leading-edge protrusions. However, recent evidence indicates that actin flows correlate better with directed motion than protrusions. A unified chemotaxis model that integrates the role of protrusions and actin flows and that accounts for in vivo cell motion patterns is lacking. Here, we provide direct experimental evidence of how neutrophils sense gradients in real-time in vivo and demonstrate a two-stage process: first a ‘search’ phase, that requires actin network expansion by Arp2/3, whereby cells slow down, explore the environment and execute path corrections. This is followed by a ‘run’ phase, that requires Myosin-II-driven contractility and fast actin flows, whereby cells accelerate and persist in the source direction. Thus, protrusive forces support chemotaxis by enhancing signal detection, while actin flows act as the ultimate output of gradient processing.