title: The P2X1 receptor is required for neutrophil extravasation during lipopolysaccharide-induced lethal endotoxemia in mice.
abstract: Extracellular ATP is becoming increasingly recognized as an important regulator of inflammation. However, the known repertoire of P2 receptor subtypes responsible for the proinflammatory effects of ATP is sparse. We looked at whether the P2X1 receptor, an ATP-gated cation channel present on platelets, neutrophils, and macrophages, participates in the acute systemic inflammation provoked by LPS. Compared with wild-type (WT) mice, P2X1(-/-) mice displayed strongly diminished pathological responses, with dampened neutrophil accumulation in the lungs, less tissue damage, reduced activation of coagulation, and resistance to LPS-induced death. P2X1 receptor deficiency also was associated with a marked reduction in plasma levels of the main proinflammatory cytokines and chemokines induced by LPS. Interestingly, macrophages and neutrophils isolated from WT and P2X1(-/-) mice produced similar levels of proinflammatory cytokines when stimulated with LPS in vitro. Intravital microscopy revealed a defect in LPS-induced neutrophil emigration from cremaster venules into the tissues of P2X1(-/-) mice. Using adoptive transfer of immunofluorescently labeled neutrophils from WT and P2X1(-/-) mice into WT mice, we demonstrate that the absence of the P2X1 receptor on neutrophils was responsible for this defect. This study reveals a major role for the P2X1 receptor in LPS-induced lethal endotoxemia through its critical involvement in neutrophil emigration from venules.
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and.
authors.forename: Blandine
authors.initials: B
authors.lastname: Maître
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Magnenat
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and.
authors.forename: Véronique
authors.initials: V
authors.lastname: Heim
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ravanat
authors.affiliation: Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Evans
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and.
authors.forename: Henri
authors.initials: H
authors.lastname: de la Salle
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.affiliation: Unité Mixte de Recherche S949, INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, F-67065 Strasbourg, France; and beatrice.hechler@efs-alsace.fr.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Hechler
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D058474:Receptors, Purinergic P2X1 / Q000235:genetics / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D058474:Receptors, Purinergic P2X1