The alarmins IL-33 and HMGB1 (high mobility group box 1) play a role in type 2 inflammation and asthma pathophysiology. To see if the P2Y13 receptor (P2Y13-R), a purinergic G protein-coupled receptor (GPCR) and asthma risk allele, controls IL-33 and HMGB1 secretion. Biopsies of the bronchial mucosa were taken from healthy and asthmatic patients. The nuclear-to-cytoplasmic translocation and release of alarmins were evaluated by immunohistochemistry and ELISA in primary human airway epithelial cells (AECs), primary mouse (m)AECs, or C57Bl/6 mice infected with various aeroallergens or respiratory viruses. The role of P2Y13-R in AEC function and the start, development, and exacerbation of experimental asthma was investigated using pharmacological antagonists and P2Y13-R gene-deleted mice.

The extracellular release of ADP and ATP, nucleotides that activate P2Y13-R was stimulated by aeroallergen exposure. The nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1 were stimulated by ATP, ADP, aeroallergen (house dust mite, cockroach, or Alternaria) or viral infection, and this reaction was blocked by genetic deletion or pharmacological antagonism of P2Y13. In a high-fidelity experimental model of chronic asthma in mice, preventive or therapeutic P2Y13-R blockage reduced asthma onset and, more importantly, decreased the severity of a rhinovirus-associated exacerbation. Furthermore, antiviral immunity was depressed by P2Y13-R antagonism, which increased IFN-production and decreased viral copies in the lungs. P2Y13-R is identified as a novel gatekeeper for the nuclear alarmins IL-33 and HMGB1. Researchers show that genetic deletion or therapy with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.