Asthma and lower airway diseaseMicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2
Graphical abstract
Section snippets
Methods
The murine model of established AAD, dexamethasone treatment, respiratory tract infections in established AAD, miR-21 and PI3K inhibition, airway inflammation, AHR, quantification of mRNA and miR-21 expression, miR-21 in situ hybridization, immunoblot analyses, and statistics25, 31, 39, 44, 45, 46, 47, 48, 49, 50, 51, 52 are described in the Methods section, and Figs E1-E5 and Table E1 in this article's Online Repository at www.jacionline.org.
Chlamydia respiratory tract infection induces SSIAAD
OVA-induced AAD was established in BALB/c mice, which were then infected with Chlamydia muridarum (Cmu; see Fig E1). This is a natural mouse respiratory pathogen and the most appropriate Chlamydia strain for studying host-pathogen relationships in mice.28, 47, 53, 54, 55, 56, 57 Infection and inflammation peak at days 10 and 15, respectively.47, 53 Disease features in OVA-induced AAD wane over time (unpublished data), and therefore to assess the effect of infection, we recapitulated the asthma
Discussion
We developed novel experimental models of SSI asthma that are driven by bacterial (Chlamydia and Haemophilus) and viral (influenza and RSV) respiratory tract infections. These models recapitulate the hallmark features of this form of human asthma, including exaggerated TH1/TH17 responses and steroid-insensitive airway inflammation and AHR. By interrogating our models and using an antagomir that specifically depletes miR-21 and the pan-PI3K inhibitor LY294002, we demonstrate that
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Supported by grants and fellowships from the National Health and Medical Research Council of Australia, the University of Newcastle, the Asthma Foundation New South Wales, and the Rebecca Cooper Medical Research Foundation.
Disclosure of potential conflict of interest: R. Y. Kim, J. C. Horvat, J. W. Pinkerton, M. R. Starkey, and A. T. Essilfie have received grants from the National Health and Medical Research Council and Hunter Medical Research Institute. J. R. Mayall, P. M. Nair, N. G. Hansbro, B. Jones, T. J. Haw, K. P. Sunkara, T. H. Nguyen, and A. G. Jarnicki have received grants from the National Health and Medical Research Council. S. Keely has received grants from the National Health and Medical Research Council and the Cancer Institute of New South Wales and has consultant arrangements with Janssen Pharmaceutics, Aetheria Therapeutics, FX Medicine, the National Health and Medical Research Council, and the French Research Agency. J. Mattes has received grants from the National Health and Medical Research Council, the Hunter Medical Research Institute, Asthma Australia, and Rebecca L Cooper Medical Research Foundation Ltd. I. M. Adcock has received grants from the Wellcome Trust and the European Union–Innovative Medicine Initiative, the European Union H2020, Boehringer Ingelheim, the Medical Research Council, the British Heart Foundation, and DMT; is a board member for Almirall; has received payment for lectures from Merck Sharp & Dohme; has received payment for educational presentations from Thomson Reuters; and has received travel support from Boehringer Ingelheim, GlaxoSmithKline, and Merck Sharp & Dohme. P. S. Foster and P. M. Hansbro have received grants from the National Health and Medical Research Council, the Hunter Medical Research Institute, and the Australian Research Council.
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These authors contributed equally to this work.