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Targeting the P2Y13 receptor suppresses IL-33 and HMGB1 release and ameliorates experimental asthma


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, Targeting the P2Y13 receptor suppresses IL-33 and HMGB1 release and ameliorates experimental asthma, American Journal of Respiratory and Critical Care Medicine, 205, (3) pp. 300-312. ISSN 1073-449X (2022) [Refereed Article]

Copyright Statement

Copyright 2022 by the American Thoracic Society

DOI: doi:10.1164/rccm.202009-3686OC


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 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.

Item Details

Item Type:Refereed Article
Keywords:asthma, COPD, infections, alarmin, purinergic, GPCR, respiratory epithelium, rhinovirus, pneumonia virus of mice
Research Division:Biomedical and Clinical Sciences
Research Group:Cardiovascular medicine and haematology
Research Field:Cardiology (incl. cardiovascular diseases)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Lu, W (Dr Monica Lu)
UTAS Author:Sohal, SS (Dr Sukhwinder Sohal)
ID Code:148749
Year Published:2022
Web of Science® Times Cited:8
Deposited By:Health Sciences
Deposited On:2022-02-06
Last Modified:2022-11-02

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