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, Susan S. Smyth

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

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 αMβ2-integrin-dependent PMN recruitment by activated platelets under (patho)physiologic conditions. Activation-dependent epitopes in β2 integrin were exposed at the contact sites between PMNs and platelets and were abolished by SFK inhibitors. PMNs from αMβ2-/-,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 αMβ2 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 αMβ2-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.

Original languageEnglish
Pages (from-to)2461-2469
Number of pages9
JournalBlood
Volume109
Issue number6
DOIs
StatePublished - Mar 15 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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