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

Werder, RB, Ullah, MA, Rahman, MM, Simpson, J, Lynch, JP, Collinson, N, Rittchen, S, Rashid, RB, Sikder, MAA, Handoko, HY, Curren, BF, Sebina, I, Hartel, G, Bissell, A, Ngo, S, Yarlagadda, T, Hasnain, SZ, Lu, W ORCID: 0000-0003-1550-2276, Sohal, SS ORCID: 0000-0001-9627-6498, Martin, M, Bowler, S, Burr, LD, Martinez, LO, Robaye, B, Spann, K, Ferreira, MAR and Phipps, S 2022 , 'Targeting the P2Y13 receptor suppresses IL-33 and HMGB1 release and ameliorates experimental asthma' , American Journal of Respiratory and Critical Care Medicine, vol. 205, no. 3 , pp. 300-312 , doi: 10.1164/rccm.202009-3686OC.

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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: 10.1164/rccm.202009-3686OC
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Copyright © 2022 by the American Thoracic Society

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