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

ABSTRACT: 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.

SUBMITTER: Chang CW 

PROVIDER: S-EPMC9117564 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature