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Targeting the P2Y13 receptor suppresses IL-33 and HMGB1 release and ameliorates experimental asthma
Citation
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
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 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 |
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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 |
Downloads: | 0 |
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