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.

Identification of P2Y receptors involved in oleamide-suppressing inflammatory responses in murine microglia and human dendritic cells

“…The endocannabinoid system including CB2 in DCs is involved in the suppression of inflammatory response 34 . It has also been reported that, upon activation by ATP, P2Y11 suppresses the inflammatory response in DCs 35,36 . Extracellular ATP induces DCs to differentiate into an anti-inflammatory type and suppresses the secretion of pro-inflammatory cytokines, including IL-12p70 and IL-6 via P2Y11; 36 in addition, NF546, a P2Y11-selective agonist, suppresses IL-12p70 production 35 .…”

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets

“…Studies of microarray analysis of ATP‐stimulated human DCs have revealed induction of thrombospondin 1 and indoleamine 2.3‐dioxygenase (IDO), two immunosuppressive genes, suggesting an important role for ATP in promoting immunotolerance . This specific role of eATP in favoring immunotolerance by conferring immunosuppressive properties to DCs has been also supported by data showing no impacts of ATP on IL‐10 but rather selectively dampening pro‐inflammatory cytokine secretion . In the context of TME, recent studies have proposed a role for eATP in the activation of the NLRP3 inflammasome in DCs through P2X7R …”

Origin and Consequences of Necroinflammation

“…Along these lines, ATP appears to be implicated in activation of the NLRP3 inflammasome (212,257,393,560,632,668). Interestingly, a recent study on the hypoxia/ reoxygenation model found that eATP was able to induce maturation of human monocyte-derived DCs (74).…”