1. Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma
- Author
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Rhiannon B Werder, Sukhwinder Singh Sohal, Bodie F Curren, Jennifer Simpson, Lucy D. Burr, Ashik Ullah, Tejasri Yarlagadda, Simon D. Bowler, Natasha Collinson, Herlina Y. Handoko, Gunter Hartel, Megan L. Martin, Kirsten Spann, Ismail Sebina, Sumaira Z. Hasnain, Bernard Robaye, Manuel A. R. Ferreira, Laurent O. Martinez, Muhammed Mahfuzur Rahman, Sonja Rittchen, Wenying Lu, Ridwan B Rashid, Alec Bissell, Simon Phipps, Sylvia Ngo, Jason P. Lynch, and Al Amin Sikder
- Subjects
Pulmonary and Respiratory Medicine ,House dust mite ,biology ,business.industry ,Purinergic receptor ,Inflammation ,Critical Care and Intensive Care Medicine ,medicine.disease ,biology.organism_classification ,HMGB1 ,respiratory tract diseases ,Pathogenesis ,Interleukin 33 ,Immunology ,biology.protein ,Medicine ,medicine.symptom ,business ,Receptor ,Asthma - 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 receptor (P2Y13-R), a purinergic G protein-coupled receptor (GPCR) and risk allele for asthma, regulates the release of IL-33 and HMGB1. METHODS Bronchial biopsies were obtained from healthy and asthmatic subjects. Primary human airway epithelial cells (AECs), primary mouse (m)AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins measured by immunohistochemistry and ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and an exacerbation of experimental asthma, was assessed using pharmacological antagonists and P2Y13-R gene-deleted mice. MEASUREMENTS AND MAIN RESULTS Aeroallergen-exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, aeroallergen (house dust mite, cockroach or Alternaria) 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.
- Published
- 2022
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