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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2461-2469.
Prepublished online as a Blood First Edition Paper on November 9, 2006; DOI 10.1182/blood-2006-06-029082.
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Submitted June 13, 2006
Accepted October 30, 2006
Src family kinases mediate neutrophil adhesion to adherent platelets
Virgilio Evangelista*, Zehra Pamuklar, Antonio Piccoli, Stefano Manarini, Giuseppe Dell'Elba, Romina Pecce, Nicola Martelli, Lorenzo Federico, Mauricio Rojas, Giorgio Berton, Clifford A Lowell, Licia Totani, and Susan S Smyth
Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Chieti, Italy
Division of Cardiovascular Medicine, The Gill Heart Institute, The University of Kentucky, Lexington, KY, United States
Carolina Cardiovascular Biology Center, The University of North Carolina, Durham, NC, United States
Department of Pathology, University of Verona, Verona, Italy
Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA, United States
Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Cheiti, Italy
* Corresponding author; email: evangelista{at}negrisud.it.
Polymorphonuclear leukocyte (PMN)-platelet interactions at sites of vascular damage contribute to local and systemic inflammation. We sought to determine the role of ''outside-in'' signaling by Src-family-kinases (SFK) in the regulation of M 2 integrin-dependent PMN recruitment by activated platelets under (patho)physiologic conditions. Activation-dependent epitopes in integrin 2 were exposed at the contacts sites between PMNs and platelets and were abolished by SFK inhibitors. PMNs from M 2-/-, hck-/-fgr-/- and hck-/-fgr-/-lyn-/- mice had an impaired capacity to adhere with activated platelets in suspension. Phosphorylation of Pyk2 accompanied PMN adhesion to platelets and was blocked by functional inhibition as well as by genetic deletion of M 2 integrin and SFKs. A Pyk2 inhibitor reduced platelet-PMN adhesion, indicating that Pyk2 may be a down-stream effector of SFKs. Analysis of PMN-platelet interactions under flow revealed that SFK signaling was required for M 2-mediated shear resistant adhesion of PMNs to adherent platelets, but was dispensable for P-selectin-PSGL-1-mediated recruitment and rolling. Finally, SFK activity was required to support PMN accumulation along adherent platelets at the site of vascular injury, in vivo. These results definitely establish a role for SFK in PMN recruitment by activated platelets and suggest novel targets to disrupt the pathophysiologic consequences of platelet-leukocyte interactions in vascular disease.

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