Selectins and chemokines use shared and distinct signals to activate β2 integrins in neutrophils

Blood Adv. 2018 Apr 10;2(7):731-744. doi: 10.1182/bloodadvances.2017015602.


Rolling neutrophils receive signals while engaging P- and E-selectin and chemokines on inflamed endothelium. Selectin signaling activates β2 integrins to slow rolling velocities. Chemokine signaling activates β2 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 γ (PIP5Kγ90)-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 PIP5Kγ90 lacking the talin-binding domain (PIP5Kγ87) could not activate integrins. Chemokines, but not selectins, used phosphatidylinositol-4,5-bisphosphate 3-kinase γ (PI3Kγ) 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 β2 integrins without selectin signals. When chemokines were limiting, they synergized with selectins to activate β2 integrins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD18 Antigens / metabolism*
  • Chemokines / metabolism
  • Chemokines / physiology*
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism
  • Humans
  • Leukocyte Rolling*
  • Mice
  • Neutrophils / chemistry
  • Neutrophils / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Selectins / metabolism
  • Selectins / physiology*
  • Signal Transduction / physiology
  • rap1 GTP-Binding Proteins / metabolism


  • CD18 Antigens
  • Chemokines
  • Selectins
  • Phosphotransferases (Alcohol Group Acceptor)
  • Class Ib Phosphatidylinositol 3-Kinase
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • rap1 GTP-Binding Proteins