MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2 - 18/04/17
Abstract |
Background |
Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease.
Objective |
We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches.
Methods |
Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated.
Results |
Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21–specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens.
Conclusion |
We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Severe asthma, corticosteroids, airway hyperresponsiveness, miR-21, PI3 kinase, histone deacetylase 2, Chlamydia species, Haemophilus influenzae, influenza, respiratory syncytial virus
Abbreviations used : AAD, AHR, Ant-21, Cmu, COPD, DEX, DMSO, Flu, GR, HDAC, Hinf, miRNA, OVA, pAKT, PI3K, PTEN, RSV, Scram, SPG, SSI, SSIAAD, STAT
Plan
| 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. |
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| 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. |
Vol 139 - N° 2
P. 519-532 - février 2017 Retour au numéro
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