Gα13 Mediates Transendothelial Migration of Neutrophils by Promoting Integrin-Dependent Motility without Affecting Directionality

Neutrophil migration requires β2 integrins and chemoattractant receptor signaling for motility and directionality. G protein subunit Gα13 can facilitate cell migration by mediating RhoA activation induced by G protein–coupled receptors. However, the possible role of Gα13-integrin interaction in migration is unclear. In this study, we show that Gα13−/− neutrophils are deficient in transendothelial migration and migration on β2 integrin ligand ICAM-1. However, unlike G protein–coupled receptors and integrin inside-out signaling pathways, Gα13 is important in migration velocity and neutrophil spreading but not in directionality nor cell adhesion. Importantly, neutrophil recruitment in vivo was also inhibited in Gα13−/− mice, suggesting the importance of Gα13 in transendothelial migration of neutrophils in vitro and in vivo. Furthermore, a synthetic peptide (MB2mP6) derived from the Gα13 binding site of β2 inhibited Gα13-β2 interaction and Gα13-mediated transient RhoA inhibition in neutrophils, suggesting that this peptide inhibited integrin outside-in signaling. MB2mP6 inhibited migration of control neutrophils through endothelial cell monolayers or ICAM-1–coated filters, but was without further effect on Gα13−/− neutrophils. It also inhibited integrin-dependent neutrophil migration velocity without affecting directionality. In vivo, MB2mP6 markedly inhibited neutrophil infiltration into the cardiac tissues induced by ischemia/reperfusion injury. Thus, Gα13-dependent outside-in signaling enables integrin-dependent neutrophil motility without affecting directionality and may be a new therapeutic target for inhibiting neutrophil trafficking but not adhesion. Key Points Gα13 plays a role in integrin-dependent neutrophil transendothelial migration. Gα13 enhances motility but did not affect directionality of neutrophil migration. Integrin outside-in signaling mediates Gα13-dependent neutrophil migration.