• Rhiannon B Werder, Md Ashik Ullah, Muhammed Mahfuzur Rahman, Jennifer Simpson, Jason P Lynch, Natasha Collinson, Sonja Rittchen, Ridwan B Rashid, Md Al Amin Sikder, Herlina Y Handoko, Bodie F Curren, Ismail Sebina, Gunter Hartel, Alec Bissell, Sylvia Ngo, Tejasri Yarlagadda, Sumaira Z Hasnain, Wenying Lu, Sukhwinder S Sohal, Megan Martin, Simon Bowler, Lucy D Burr, Laurent O Martinez, Bernard Robaye, Kirsten Spann, FerreiraManuel A RMAR0000-0001-9059-1825Respiratory Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., and Simon Phipps.
• Respiratory Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
• Am. J. Respir. Crit. Care Med. 2022 Feb 1; 205 (3): 300-312.

AbstractRationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y13-R (P2Y13 receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Methods: Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma. Primary human airway epithelial cells (AECs), primary mouse AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins was measured by using immunohistochemistry and an ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y13-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, and aeroallergen (house dust mite, cockroach, or Alternaria antigen) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y13-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung. Conclusions: We identify P2Y13-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1 and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.

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