Endogenous UDP-Glc acts through the purinergic receptor P2RY14 to exacerbate eosinophilia and airway hyperresponsiveness in a protease model of allergic asthma

Abstract

Abstract Human asthma represents a wide spectrum of pathologies that likely arise through distinct molecular pathways, and a major therapeutic goal is to target individual therapies to specific forms, or endotypes, of this disease. Here we studied the role of UDP-glucose (UDP-Glc), an alarmin which we found to be released into the airways of allergen-sensitized mice upon their subsequent challenge with allergen. UDP-Glc signals through the purinergic receptor, P2Y14R, and mice lacking this receptor display marked attenuation of both eosinophilia and airway hyperresponsiveness (AHR) in a protease model of allergic asthma. By contrast, these features of asthma were similar in wild type and P2ry14-deficient mice in a TLR-ligand model of asthma, indicating an endotype-specific role for UDP-Glc and P2Y14R. Importantly, administrationof PPTN, a small molecule antagonist of P2Y14R, also led to reduction of airway inflammation and AHR in the protease mediated asthma. Although its mechanism of action remains unclear, P2ry14 was most highly expressed in recruited eosinophils and neutrophils, suggesting UDP-Glc acts directly on these cells. Our current findings suggest that antagonists of P2Y14R might be selectively used to control asthma exacerbations in specific forms of human asthma.