The Journal of Experimental Medicine
ThymUS '08
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Published 4 October 2004. doi:10.1084/jem.20040424
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 7, 935-939
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Brief Definitive Report

 CXCR2- and E-Selectin–induced Neutrophil Arrest during Inflammation In Vivo

Michael L. Smith1, Timothy S. Olson2, and Klaus Ley1,2,3

1 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908
2 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908
3 Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908

Address correspondence to Klaus Ley, Cardiovascular Research Center, P.O. Box 801394, University of Virginia Health Science Center, Charlottesville, VA 22908. Phone: (434) 243-9966; Fax: (434) 924-2828; email: klausley{at}virginia.edu

The signaling events leading to the activation of integrins and firm arrest of rolling neutrophils in inflamed venules have yet to be elucidated. In vitro assays suggest that both E-selectin and chemokines can trigger arrest of rolling neutrophils, but E-selectin–/– mice have normal levels of adherent neutrophils in inflamed venules. To test whether chemokine-induced neutrophil arrest in vivo can be unmasked by blocking E-selectin, we investigated neutrophil adhesion in inflamed cremaster muscle venules in tumor necrosis factor (TNF)-{alpha}–treated CXCR2–/– or wild-type (WT) mice injected with E-selectin blocking monoclonal antibody (mAb) 9A9. To block chemokine receptor signaling, we investigated E-selectin–/– or WT mice treated with pertussis toxin (PTx) intravenously. Neutrophil adhesion was unchanged in CXCR2–/–, E-selectin–/–, PTx-treated WT, or mAb 9A9–treated WT mice. However, TNF-{alpha}–induced neutrophil adhesion was almost completely abrogated in E-selectin–/– mice treated with PTx and significantly reduced in CXCR2–/– mice treated with the E-selectin blocking mAb. In thioglycollate-induced peritonitis, PTx treatment blocked neutrophil recruitment into the peritoneum of E-selectin–/– mice, but had only a partial effect in WT animals. These data show that E-selectin– and chemokine-mediated arrest mechanisms are overlapping in this model and identify CXCR2 as an important neutrophil arrest chemokine in vivo.

Key Words: E-selectin • chemokine • neutrophils • G protein–coupled receptors • pertussis toxin

M.L. Smith and T.S. Olson contributed equally to this work.


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