Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Targeting the P2Y13 receptor suppresses IL-33 and HMGB1 release and ameliorates experimental asthma (#12)

Rhiannon B. Werder 1 2 3 4 , Md Ashik Ullah 4 , Muhammed Mahfuzur Rahman 1 4 , Jennifer Simpson 1 4 5 , Jason P. Lynch 4 6 , Natasha Collinson 4 , Sonja Rittchen 4 7 , Ridwan B. Rashid 1 4 , Md. Al Amin Sikder 1 4 , Wenying Lu 8 , Sukhwinder S. Sohal 8 , Laurent Martinez 9 , Bernard Robaye 10 , Kirsten Spann 11 , Manuel A.R. Ferreira 4 , Simon Phipps 1 4 12
  1. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  2. Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA, USA
  3. The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
  4. QIMR Berghofer Medical Research Institute, Brisbane, QUEENSLAND, Australia
  5. Barrier Immunity Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  6. Department of Microbiology, Harvard Medical School, Boston, MA, USA
  7. Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
  8. Respiratory Translational Research Group, Department of Laboratory Medicine, University of Tasmania, Launceston, Tasmania, Australia
  9. Institut National de la Santé et de la Recherche Médicale (INSERM), University of Toulouse, Toulouse, France
  10. IRIBHM Free University of Brussels, Brussels, Gosselies, Belgium
  11. School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
  12. Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, Australia

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 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 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, 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.