P-selectin primes leukocyte integrin activation during inflammation

Nat Immunol. 2007 Aug;8(8):882-92. doi: 10.1038/ni1491. Epub 2007 Jul 15.

Abstract

Selectins mediate leukocyte rolling and prime leukocytes for integrin-mediated leukocyte adhesion. However, neither the in vivo importance of nor the signaling pathway by which selectin-mediated integrin activation occurs has been determined. We report here that P-selectin-deficient mice manifested impaired leukocyte adhesion, which was 'rescued' by soluble P-selectin. Mechanistically, the cytoplasmic domain of P-selectin glycoprotein ligand 1 formed a constitutive complex with Nef-associated factor 1. After binding of P-selectin, Src kinases phosphorylated Nef-associated factor 1, which recruited the phosphoinositide-3-OH kinase p85-p110delta heterodimer and resulted in activation of leukocyte integrins. Inhibition of this signal-transduction pathway diminished the adhesion of leukocytes to capillary venules and suppressed peritoneal infiltration of leukocytes. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by P-selectin glycoprotein ligand 1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / immunology
  • Chemotaxis, Leukocyte / physiology*
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Integrins / immunology*
  • Integrins / metabolism
  • Leukocytes / immunology*
  • Leukocytes / metabolism
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • P-Selectin / immunology*
  • P-Selectin / metabolism
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction / immunology*
  • Transfection

Substances

  • DNA-Binding Proteins
  • Integrins
  • Membrane Glycoproteins
  • P-Selectin
  • P-selectin ligand protein
  • TNIP1 protein, human
  • Phosphatidylinositol 3-Kinases