MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2

Richard Y. Kim, Jay C. Horvat, James W. Pinkerton, Malcolm R. Starkey, Ama T. Essilfie, Jemma R. Mayall, Prema M. Nair, Nicole G. Hansbro, Bernadette Jones, Tatt Jhong Haw, Krishna P. Sunkara, Thi Hiep Nguyen, Andrew G. Jarnicki, Simon Keely, Joerg Mattes, Ian M. Adcock, Paul S. Foster, Philip M. Hansbro

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110 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)519-532
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number2
DOIs
Publication statusPublished - 1 Feb 2017
Externally publishedYes

Keywords

  • airway hyperresponsiveness
  • Chlamydia species
  • corticosteroids
  • Haemophilus influenzae
  • histone deacetylase 2
  • influenza
  • miR-21
  • PI3 kinase
  • respiratory syncytial virus
  • Severe asthma

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