title: P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice.
abstract: Adenosine triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophil (PMN) functions. PMNs have recently been implicated in the initiation of thrombosis. We investigated the role of ATP and adenosine in PMN activation and recruitment at the site of endothelial injury. Following binding to the injured vessel wall, PMNs are activated and release elastase. The recruitment of PMNs and the subsequent fibrin generation and thrombus formation are strongly affected in mice deficient in the P2X1-ATP receptor and in wild-type (WT) mice treated with CGS 21680, an agonist of the A2A adenosine receptor or NF449, a P2X1 antagonist. Infusion of WT PMNs into P2X1-deficient mice increases fibrin generation but not thrombus formation. Restoration of thrombosis requires infusion of both platelets and PMNs from WT mice. In vitro, ATP activates PMNs, whereas CGS 21680 prevents their binding to activated endothelial cells. These data indicate that adenosine triphosphate (ATP) contributes to polymorphonuclear neutrophil (PMN) activation leading to their adhesion at the site of laser-induced endothelial injury, a necessary step leading to the generation of fibrin, and subsequent platelet-dependent thrombus formation. Altogether, our study identifies previously unknown mechanisms by which ATP and adenosine are key molecules involved in thrombosis by regulating the activation state of PMNs.
authors.affiliation: Aix Marseille Université, Marseille, France;
authors.forename: Roxane
authors.initials: R
authors.lastname: Darbousset
authors.affiliation: Groupe Interdisciplinaire Génoprotéomique Appliquée-Research, Laboratory of Thrombosis and Hemostasis, University of Liège, Liège, Belgium;
authors.forename: Céline
authors.initials: C
authors.lastname: Delierneux
authors.affiliation: Aix Marseille Université, Marseille, France;
authors.forename: Soraya
authors.initials: S
authors.lastname: Mezouar
authors.affiliation: Groupe Interdisciplinaire Génoprotéomique Appliquée-Research, Laboratory of Thrombosis and Hemostasis, University of Liège, Liège, Belgium;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hego
authors.affiliation: Groupe Interdisciplinaire Génoprotéomique Appliquée-Research, Laboratory of Thrombosis and Hemostasis, University of Liège, Liège, Belgium;
authors.forename: Christelle
authors.initials: C
authors.lastname: Lecut
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Guillaumat
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland;
authors.forename: Markus A
authors.initials: MA
authors.lastname: Riederer
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Evans
authors.affiliation: Aix Marseille Université, Marseille, France; Laboratoire d'Hématologie, Centre Hospitalo-Universitaire Conception, Marseille, France; and.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.affiliation: Aix Marseille Université, Marseille, France;
authors.forename: Laurence
authors.initials: L
authors.lastname: Panicot-Dubois
authors.affiliation: Groupe Interdisciplinaire Génoprotéomique Appliquée-Research, Laboratory of Thrombosis and Hemostasis, University of Liège, Liège, Belgium;
authors.forename: Cécile
authors.initials: C
authors.lastname: Oury
authors.affiliation: Aix Marseille Université, Marseille, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Dubois
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D005337:Fibrin / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058474:Receptors, Purinergic P2X1 / Q000235:genetics* / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058474:Receptors, Purinergic P2X1; D005337:Fibrin