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Abstract

Rationale: 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 proteincoupled 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.

Item Type:	Article
Authors/Creators:	Werder, RB and Ullah, MA and Rahman, MM and Simpson, J and Lynch, JP and Collinson, N and Rittchen, S and Rashid, RB and Sikder, MAA and Handoko, HY and Curren, BF and Sebina, I and Hartel, G and Bissell, A and Ngo, S and Yarlagadda, T and Hasnain, SZ and Lu, W and Sohal, SS and Martin, M and Bowler, S and Burr, LD and Martinez, LO and Robaye, B and Spann, K and Ferreira, MAR and Phipps, S
Keywords:	asthma, COPD, infections, alarmin, purinergic, GPCR, respiratory epithelium, rhinovirus, pneumonia virus of mice
Journal or Publication Title:	American Journal of Respiratory and Critical Care Medicine
Publisher:	Amer Thoracic Soc
ISSN:	1073-449X
DOI / ID Number:	https://doi.org/10.1164/rccm.202009-3686OC
Copyright Information:	Copyright © 2022 by the American Thoracic Society
Related URLs:	Google Scholar: Sohal, SS UTAS Profile: Sohal, SS
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