Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1

Immunity. 2007 Jun;26(6):773-83. doi: 10.1016/j.immuni.2007.04.011. Epub 2007 May 31.

Abstract

Engagement of neutrophils by E-selectin results in integrin activation. Here, we investigated primary mouse neutrophils in whole blood by using intravital microscopy and autoperfused flow chambers. Slow rolling on E-selectin coimmobilized with intercellular adhesion molecule-1 (ICAM-1) required P-selectin glycoprotein ligand (PSGL)-1, was dependent on alpha(L)beta(2) integrin (LFA-1), and required continuous E-selectin engagement. Slow rolling was abolished by pharmacological blockade of spleen tyrosine kinase (Syk) and was absent in Syk(-/-) bone-marrow chimeric mice. Treatment with tumor necrosis factor-alpha lowered rolling velocity further and induced CXC chemokine ligand-1 (CXCL1) and CXC chemokine receptor-2 (CXCR2)-dependent leukocyte arrest on E-selectin and ICAM-1. Arrest but not rolling was blocked by an allosteric inhibitor of LFA-1 activation. Neutrophil recruitment in a thioglycollate-induced peritonitis model was almost completely inhibited in Selplg(-/-) mice or Syk(-/-) bone-marrow chimeras treated with pertussis toxin. This identifies a second neutrophil-activation pathway that is as important as activation through G protein-coupled receptors (GPCRs).

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion
  • Chemokine CXCL1
  • Chemokines, CXC / metabolism
  • E-Selectin / immunology
  • Intercellular Adhesion Molecule-1 / immunology
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Leukocyte Rolling* / drug effects
  • Lymphocyte Function-Associated Antigen-1 / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Neutrophils / enzymology
  • Neutrophils / immunology*
  • Peritonitis / chemically induced
  • Peritonitis / immunology
  • Pertussis Toxin / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / physiology*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Interleukin-8B / metabolism
  • Syk Kinase
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Chemokine CXCL1
  • Chemokines, CXC
  • Cxcl1 protein, mouse
  • E-Selectin
  • Intracellular Signaling Peptides and Proteins
  • Lymphocyte Function-Associated Antigen-1
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • Receptors, G-Protein-Coupled
  • Receptors, Interleukin-8B
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Pertussis Toxin
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse