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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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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Src family kinases mediate neutrophil adhesion to adherent platelets
Virgilio Evangelista1,
Zehra Pamuklar2,
Antonio Piccoli1,
Stefano Manarini1,
Giuseppe Dell'Elba1,
Romina Pecce1,
Nicola Martelli1,
Lorenzo Federico2,
Mauricio Rojas3,
Giorgio Berton4,
Clifford A. Lowell5,
Licia Totani1, and
Susan S. Smyth2
1 Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud;
2 Division of Cardiovascular Medicine, The Gill Heart Institute, The University of Kentucky, Lexington;
3 Carolina Cardiovascular Biology Center, The University of North Carolina, Chapel Hill;
4 Department of Pathology, University of Verona, Italy;
5 Department of Laboratory Medicine, University of California at San Francisco
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 tyrosine kinases (SFKs) in the regulation of  Mß2-integrin–dependent PMN recruitment by activated platelets under (patho)physiologic conditions. Activation-dependent epitopes in ß2 integrin were exposed at the contact sites between PMNs and platelets and were abolished by SFK inhibitors. PMNs from Mß2–/–, 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 inhibition as well as by genetic deletion of Mß2 integrin and SFKs. A Pyk2 inhibitor reduced platelet-PMN adhesion, indicating that Pyk2 may be a downstream effector of SFKs. Analysis of PMN-platelet interactions under flow revealed that SFK signaling was required for Mß2-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 SFKs 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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