P-selectin primes leukocyte integrin activation during inflammation.
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.
Mesh Terms:
Animals, Cell Adhesion, Chemotaxis, Leukocyte, DNA-Binding Proteins, Humans, Immunoblotting, Immunoprecipitation, Inflammation, Integrins, Leukocytes, Membrane Glycoproteins, Mice, P-Selectin, Phosphatidylinositol 3-Kinases, Signal Transduction, Transfection
Animals, Cell Adhesion, Chemotaxis, Leukocyte, DNA-Binding Proteins, Humans, Immunoblotting, Immunoprecipitation, Inflammation, Integrins, Leukocytes, Membrane Glycoproteins, Mice, P-Selectin, Phosphatidylinositol 3-Kinases, Signal Transduction, Transfection
Nat. Immunol.
Date: Aug. 01, 2007
PubMed ID: 17632516
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