The P2Y purinoceptor, P2Y14R, promotes AHR in an animal model of asthma

Abstract

Abstract The initiation and propagation of immune responses in the lung are mediated in part by so-called ‘alarmins’ that include nucleotides and nucleotide-sugars. Uridine diphosphate (UDP), and UDP-sugars, such as UDP-glucose (UDP-Glc) can be released by airway epithelial cells and bind to the G-protein coupled receptor, P2Y14R on leukocytes. However, the role of these molecules in allergic airway inflammation remains unclear. Our analysis of flow cytometry sorted cells from the lung revealed that P2ry14, the gene encoding P2Y14R, is primarily expressed in alveolar macrophages and in CD103+ dendritic cells. Using P2Y14R-specific agonists and antagonists, we tested whether this receptor has a role in allergic airway disease. Although we found no evidence that UDP-glucose or P2Y14R were involved in allergic sensitization through the airway, administration of UDP-Glc or agonists of P2Y14R during the allergen challenge phase acted synergistically with the inhaled allergen to promote neutrophilic inflammation. Conversely, administration of the P2Y14R antagonist, PPTN, during the challenge phase attenuated inflammation. To exclude the possibility that these results stemmed from non-specific effects or cell toxicity, we studied P2ry14-deficient mice. Compared to WT animals, P2ry14-deficient mice displayed significantly less airway hyperresponsiveness following allergen challenge. Together, these results suggest that existing antagonists of P2Y14R, or their derivatives, might be useful to control asthma exacerbations in humans.