Selectins and chemokines use shared and distinct signals to activate ?2 integrins in neutrophils.

ABSTRACT: Rolling neutrophils receive signals while engaging P- and E-selectin and chemokines on inflamed endothelium. Selectin signaling activates ?2 integrins to slow rolling velocities. Chemokine signaling activates ?2 integrins to cause arrest. Despite extensive study, key aspects of these signaling cascades remain unresolved. Using complementary in vitro and in vivo assays, we found that selectin and chemokine signals in neutrophils triggered Rap1a-dependent and phosphatidylinositol-4-phosphate 5-kinase ? (PIP5K?90)-dependent pathways that induce integrin-dependent slow rolling and arrest. Interruption of both pathways, but not either pathway alone, blocked talin-1 recruitment to and activation of integrins. An isoform of PIP5K?90 lacking the talin-binding domain (PIP5K?87) could not activate integrins. Chemokines, but not selectins, used phosphatidylinositol-4,5-bisphosphate 3-kinase ? (PI3K?) in cooperation with Rap1a to mediate integrin-dependent slow rolling (at low chemokine concentrations), as well as arrest (at high chemokine concentrations). High levels of chemokines activated ?2 integrins without selectin signals. When chemokines were limiting, they synergized with selectins to activate ?2 integrins.

SUBMITTER: Yago T 

PROVIDER: S-EPMC5894262 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature