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Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

Stéphanie Chadet 1 Fabrice Ivanes 1, 2 Lauriane Benoist 1 Charlotte Salmon-Gandonnière 3 Roseline Guibon 1 Florence Velge-Roussel 1, 4 Dominique Babuty 2, 1 Christophe Baron 1, 3, 4 Sébastien Roger 5 Denis Angoulvant 1, 2, 4, *
* Corresponding author
4 FHU SUPORT - Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation
CHU Poitiers - Centre hospitalier universitaire de Poitiers , CHRU TOURS - Centre Hospitalier Régional Universitaire de Tours, RESINFIT - Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques, CHU Limoges, IPPRITT - Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation, IRTOMIT - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques, Cellules Dendritiques, Immunomodulation et Greffes
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.
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Stéphanie Chadet, Fabrice Ivanes, Lauriane Benoist, Charlotte Salmon-Gandonnière, Roseline Guibon, et al.. Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells. Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2015, 195 (2), pp.651 - 660. ⟨10.4049/jimmunol.1500197⟩. ⟨inserm-01833561⟩