The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
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Published online
doi:10.1084/jem.20072660
The Journal of Experimental Medicine, Vol. 205, No. 10, 2339-2347
The Rockefeller University Press, 0022-1007 $30.00
© Zarbock et al.
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ARTICLE

 PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR{gamma} to induce slow leukocyte rolling

Alexander Zarbock1,3,5, Clare L. Abram4, Matthias Hundt5, Amnon Altman5, Clifford A. Lowell4, and Klaus Ley1,2,5

1 Robert M. Berne Cardiovascular Research Center, 2 Department of Biomedical Engineering, Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908
3 Department of Anesthesiology and Intensive Care Medicine, University of Münster, D-48149 Münster, Germany
4 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143
5 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

CORRESPONDENCE Klaus Ley: klaus{at}liai.org

E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the β2 integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of G{alpha}i-protein–coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)–containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin–mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr–/– or hck–/– lyn–/– fgr–/– mice. Neutrophils from Tyrobp–/– Fcrg–/– mice lacking both DAP12 and FcR{gamma} were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. G{alpha}i-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp–/– Fcrg–/– mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcR{gamma} is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.

Abbreviations used: GST, glutathione S-transferase; ICAM-1, intercellular adhesion molecule-1; ITAM, immunoreceptor tyrosine-based activating motif; PSGL-1, P-selectin glycoprotein ligand-1; Syk, spleen tyrosine kinase; TREM, triggering receptor expressed on myeloid cells.

© 2008 Zarbock et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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