TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase

Gang Liu, Tatt Jhong Haw, Malcolm R. Starkey, Ashleigh M. Philp, Stelios Pavlidis, Christina Nalkurthi, Prema M. Nair, Henry M. Gomez, Irwan Hanish, Alan CY. Hsu, Elinor Hortle, Sophie Pickles, Joselyn Rojas-Quintero, Raul San Jose Estepar, Jacqueline E. Marshall, Richard Y. Kim, Adam M. Collison, Joerg Mattes, Sobia Idrees, Alen Faiz, Nicole G. Hansbro, Ryutaro Fukui, Yusuke Murakami, Hong Sheng Cheng, Nguan Soon Tan, Sanjay H. Chotirmall, Jay C. Horvat, Paul S. Foster, Brian GG. Oliver, Francesca Polverino, Antonio Ieni, Francesco Monaco, Gaetano Caramori, Sukhwinder S. Sohal, Ken R. Bracke, Peter A. Wark, Ian M. Adcock, Kensuke Miyake, Don D. Sin and Philip M. Hansbro ()
Additional contact information
Gang Liu: University of Technology Sydney
Tatt Jhong Haw: Hunter Medical Research Institute & University of Newcastle
Malcolm R. Starkey: Monash University
Ashleigh M. Philp: University of Technology Sydney
Stelios Pavlidis: Imperial College London
Christina Nalkurthi: University of Technology Sydney
Prema M. Nair: Hunter Medical Research Institute & University of Newcastle
Henry M. Gomez: Hunter Medical Research Institute & University of Newcastle
Irwan Hanish: Hunter Medical Research Institute & University of Newcastle
Alan CY. Hsu: Hunter Medical Research Institute & University of Newcastle
Elinor Hortle: University of Technology Sydney
Sophie Pickles: University of Technology Sydney
Joselyn Rojas-Quintero: Baylor College of Medicine
Raul San Jose Estepar: Harvard Medical School
Jacqueline E. Marshall: University of Technology Sydney
Richard Y. Kim: Hunter Medical Research Institute & University of Newcastle
Adam M. Collison: Hunter Medical Research Institute & University of Newcastle
Joerg Mattes: Hunter Medical Research Institute & University of Newcastle
Sobia Idrees: University of Technology Sydney
Alen Faiz: University of Technology Sydney
Nicole G. Hansbro: University of Technology Sydney
Ryutaro Fukui: The University of Tokyo
Yusuke Murakami: Musashino University
Hong Sheng Cheng: Nanyang Technological University
Nguan Soon Tan: Nanyang Technological University
Sanjay H. Chotirmall: Nanyang Technological University
Jay C. Horvat: Hunter Medical Research Institute & University of Newcastle
Paul S. Foster: Hunter Medical Research Institute & University of Newcastle
Brian GG. Oliver: University of Sydney & School of Life Sciences, University of Technology
Francesca Polverino: Baylor College of Medicine
Antonio Ieni: Università di Messina
Francesco Monaco: Università di Messina
Gaetano Caramori: Universities of Messina and Parma
Sukhwinder S. Sohal: University of Tasmania
Ken R. Bracke: Ghent University Hospital
Peter A. Wark: Hunter Medical Research Institute & University of Newcastle
Ian M. Adcock: UNSW Medicine and Health, St Vincent’s Healthcare clinical campus, UNSW
Kensuke Miyake: The University of Tokyo
Don D. Sin: University of British Columbia
Philip M. Hansbro: University of Technology Sydney

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: Abstract Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

Date: 2023
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DOI: 10.1038/s41467-023-42913-z

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