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SHR Neuro Cancer Cardio Lipid Metab Microb

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; Sohal, SS; Martin, M; Bowler, S; Burr, LD; Martinez, LO; Robaye, B; Spann, K; Ferreira, MAR; Phipps, S.
Targeting the P2Y₁₃ Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma.
Am J Respir Crit Care Med. 2022; 205(3):300-312 Doi: 10.1164/rccm.202009-3686OC
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Co-authors Med Uni Graz: Rittchen Sonja
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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 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.
Find related publications in this database (using NLM MeSH Indexing): Animals - administration & dosage; Asthma - immunology, metabolism, physiopathology; Biomarkers - metabolism; Case-Control Studies - administration & dosage; Disease Progression - administration & dosage; Enzyme-Linked Immunosorbent Assay - administration & dosage; Epithelial Cells - metabolism; HMGB1 Protein - metabolism; Humans - administration & dosage; Immunohistochemistry - administration & dosage; Interleukin-33 - metabolism; Mice - administration & dosage; Mice, Inbred C57BL - administration & dosage; Receptors, Purinergic P2 - metabolism
Find related publications in this database (Keywords): alarmin; purinergic; GPCR; epithelium; rhinovirus; pneumonia virus of mice

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