title: Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets.
abstract: In addition to being key elements in hemostasis and thrombosis, platelets amplify neutrophil function. We aimed to gain further insight into the stimuli, mediators, molecular pathways, and regulation of neutrophil extracellular trap formation mediated by human platelets. Platelets stimulated by lipopolysaccharide, a wall component of gram-negative bacteria, Pam3-cysteine-serine-lysine 4, a mimetic of lipopeptide from gram-positive bacteria, Escherichia coli, Staphylococcus aureus, or physiologic platelet agonists promoting neutrophil extracellular trap formation and myeloperoxidase-associated DNA activity under static and flow conditions. Although P-selectin or glycoprotein IIb/IIIa were not involved, platelet glycoprotein Ib, neutrophil cluster of differentiation 18, and the release of von Willebrand factor and platelet factor 4 seemed to be critical for the formation of neutrophil extracellular traps. The secretion of these molecules depended on thromboxane A(2) production triggered by lipopolysaccharide or Pam3-cysteine-serine-lysine 4 but not on high concentrations of thrombin. Accordingly, aspirin selectively inhibited platelet-mediated neutrophil extracellular trap generation. Signaling through extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, and Src kinases, but not p38 or reduced nicotinamide adenine dinucleotide phosphate oxidase, was involved in platelet-triggered neutrophil extracellular trap release. Platelet-mediated neutrophil extracellular trap formation was inhibited by prostacyclin. Our results support a role for stimulated platelets in promoting neutrophil extracellular trap formation, reveal that an endothelium-derived molecule contributes to limiting neutrophil extracellular trap formation, and highlight platelet inhibition as a potential target for controlling neutrophil extracellular trap cell death.
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Agostina
authors: A
authors: Carestia
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Tomás
authors: T
authors: Kaufman
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Leonardo
authors: L
authors: Rivadeneyra
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Verónica Inés
authors: VI
authors: Landoni
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Roberto Gabriel
authors: RG
authors: Pozner
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Soledad
authors: S
authors: Negrotto
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Lina Paola
authors: LP
authors: D'Atri
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
authors: Ricardo Martín
authors: RM
authors: Gómez
authors: *Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina mschattner@hotmail.com.
authors: Mirta
authors: M
authors: Schattner
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D065206:Extracellular Traps / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D055666:Lipopeptides / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D011956:Receptors, Cell Surface
keywords: TLR agonists; platelet factor 4; thromboxane A2; von Willebrand factor