Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma.
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 HMGB...
| Publicado en: | American Journal of Respiratory & Critical Care Medicine Vol. 205; no. 3; pp. 300 - 340 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Oxford University Press / USA
2/1/2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=155006359&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 155006359 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 1073449X 1FG jtl: American Journal of Respiratory & Critical Care Medicine issn: 1073449X maglogo: N pubinfo: dt: 2/1/2022 vid: 205 iid: 3 pid: 622 pub: Oxford University Press / USA artinfo: ui: 155006359 155006359 NLM34860143 155006359 10.1164/rccm.202009-3686OC NLM34860143 155006359 ppf: 300 ppct: 40 formats: tig: atl: Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma. aug: au: Werder, Rhiannon B. Ullah, Md Ashik Rahman, Muhammed Mahfuzur Simpson, Jennifer Lynch, Jason P. Collinson, Natasha Rittchen, Sonja Rashid, Ridwan B. Sikder, Md Al Amin Handoko, Herlina Y. Curren, Bodie F. Sebina, Ismail Hartel, Gunter Bissell, Alec Ngo, Sylvia Yarlagadda, Tejasri Hasnain, Sumaira Z. Wenying Lu Sohal, Sukhwinder S. Martin, Megan affil: Respiratory Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia sug: subj: Asthma Immunology Proteins Metabolism Receptors, Cell Surface Metabolism Mice Asthma Physiopathology Immunohistochemistry Disease Progression Human Epithelial Cells Metabolism Animal Studies Enzyme-Linked Immunosorbent Assay Asthma Metabolism Case Control Studies Comparative Studies Multicenter Studies Evaluation Research Validation Studies ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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