TY - JOUR
T1 - TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
AU - Liu, Gang
AU - Haw, Tatt Jhong
AU - Starkey, Malcolm R.
AU - Philp, Ashleigh M.
AU - Pavlidis, Stelios
AU - Nalkurthi, Christina
AU - Nair, Prema M.
AU - Gomez, Henry M.
AU - Hanish, Irwan
AU - Hsu, Alan Cy
AU - Hortle, Elinor
AU - Pickles, Sophie
AU - Rojas-Quintero, Joselyn
AU - Estepar, Raul San Jose
AU - Marshall, Jacqueline E.
AU - Kim, Richard Y.
AU - Collison, Adam M.
AU - Mattes, Joerg
AU - Idrees, Sobia
AU - Faiz, Alen
AU - Hansbro, Nicole G.
AU - Fukui, Ryutaro
AU - Murakami, Yusuke
AU - Cheng, Hong Sheng
AU - Tan, Nguan Soon
AU - Chotirmall, Sanjay H.
AU - Horvat, Jay C.
AU - Foster, Paul S.
AU - Oliver, Brian Gg
AU - Polverino, Francesca
AU - Ieni, Antonio
AU - Monaco, Francesco
AU - Caramori, Gaetano
AU - Sohal, Sukhwinder S.
AU - Bracke, Ken R.
AU - Wark, Peter A.
AU - Adcock, Ian M.
AU - Miyake, Kensuke
AU - Sin, Don D.
AU - Hansbro, Philip M.
N1 - Funding Information:
We thank Bradley Mitchell, Breanna Anderson, Kristy Wheeldon, and Natalie Kiaos for assistance with CS exposure models. This work was funded by the National Health and Medical Research Council (NHMRC) of Australia grants to P.M.H., B.G.G.O, P.A.W., I.M.A. and K.M. (1137995, 1023131). G.L. was supported by a CREATE Hope Scientific Fellowship from Lung Foundation Australia. M.R.S. was supported by an Australian Research Council fellowship DE170100226. R.Y.K was supported by a fellowship from the Lung Foundation Australia/Boehringer Ingelheim (2017/1). S.S.S. is supported by grants from Clifford Craig Foundation Launceston General Hospital. A.P. was supported by the Graham Painton Foundation fellowship. P.M.H. was supported by a Fellowship and grant from the NHMRC of Australia (1175134, 1137995) and by UTS.
Publisher Copyright:
© 2023, Crown.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85176384352
U2 - 10.1038/s41467-023-42913-z
DO - 10.1038/s41467-023-42913-z
M3 - Article
C2 - 37963864
AN - SCOPUS:85176384352
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7349
ER -
SDG 3 Good Health and Well-being