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

journal contribution
posted on 2023-05-21, 05:38 authored by 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, Wenying LuWenying Lu, Sukhwinder SohalSukhwinder Sohal, Martin, M, Bowler, S, Burr, LD, Martinez, LO, Robaye, B, Spann, K, Ferreira, MAR, Phipps, S

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.


Clifford Craig Foundation


Publication title

American Journal of Respiratory and Critical Care Medicine








School of Health Sciences


Amer Thoracic Soc

Place of publication

1740 Broadway, New York, USA, Ny, 10019-4374

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Copyright © 2022 by the American Thoracic Society

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Socio-economic Objectives

Diagnosis of human diseases and conditions

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