Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1.
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).
Zarbock
Alexander
A
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Lowell
Clifford A
CA
Ley
Klaus
K
D000818:Animals; D002448:Cell Adhesion; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D019040:E-Selectin / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D036904:Leukocyte Rolling / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D037342:Pertussis Toxin / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D019040:E-Selectin; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D043562:Receptors, G-Protein-Coupled; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse