title: Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells.
abstract: High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chadet
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Cardiologie, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France;
authors.forename: Fabrice
authors.initials: F
authors.lastname: Ivanes
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France;
authors.forename: Lauriane
authors.initials: L
authors.lastname: Benoist
authors.affiliation: Service de Néphrologie et d'Immunologie Clinique, Centre Hospitalier Régional Universitaire de Tours, 37000 Tours, France;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Salmon-Gandonnière
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France;
authors.forename: Roseline
authors.initials: R
authors.lastname: Guibon
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Fédération Hospitalo-Universitaire SUPPORT Tours, Poitiers, Limoges, Université François-Rabelais de Tours, 37032 Tours, France; and.
authors.forename: Florence
authors.initials: F
authors.lastname: Velge-Roussel
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Cardiologie, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Babuty
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Néphrologie et d'Immunologie Clinique, Centre Hospitalier Régional Universitaire de Tours, 37000 Tours, France; Fédération Hospitalo-Universitaire SUPPORT Tours, Poitiers, Limoges, Université François-Rabelais de Tours, 37032 Tours, France; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Baron
authors.affiliation: UMR INSERM 1069, "Nutrition, Croissance et Cancer," Université François-Rabelais de Tours, 37032 Tours, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Roger
authors.affiliation: EA 4245 Cellules Dendritiques, Immunomodulation et Greffes, Université François-Rabelais de Tours, 37032 Tours, France; Service de Cardiologie, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours, 37044 Tours, France; Fédération Hospitalo-Universitaire SUPPORT Tours, Poitiers, Limoges, Université François-Rabelais de Tours, 37032 Tours, France; and denis.angoulvant@univ-tours.fr.
authors.forename: Denis
authors.initials: D
authors.lastname: Angoulvant
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D015687:Cell Hypoxia; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D010100:Oxygen / Q000494:pharmacology*; D061251:Primary Cell Culture; D058914:Purinergic Antagonists / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; C109734:P2RY11 protein, human; D058914:Purinergic Antagonists; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D016753:Interleukin-10; D018664:Interleukin-12; D000255:Adenosine Triphosphate; D010100:Oxygen