title: MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Kim
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Horvat
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: James W
authors.initials: JW
authors.lastname: Pinkerton
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Ama T
authors.initials: AT
authors.lastname: Essilfie
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Jemma R
authors.initials: JR
authors.lastname: Mayall
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Prema M
authors.initials: PM
authors.lastname: Nair
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hansbro
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Jones
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Tatt Jhong
authors.initials: TJ
authors.lastname: Haw
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Sunkara
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Thi Hiep
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jarnicki
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Keely
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
authors.affiliation: Airways Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia. Electronic address: Philip.Hansbro@newcastle.edu.au.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000235:genetics; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D023502:Chlamydia muridarum / Q000276:immunology*; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D004351:Drug Resistance; D005786:Gene Expression Regulation; D006193:Haemophilus influenzae / Q000276:immunology*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011014:Pneumonia / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology
chemical_list: D000070416:Antagomirs; D003907:Dexamethasone; D056464:Histone Deacetylase 2; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C531950:MIRN21 microRNA, mouse; C487757:Pten protein, mouse
keywords: Chlamydia species; Haemophilus influenzae; PI3 kinase; Severe asthma; airway hyperresponsiveness; corticosteroids; histone deacetylase 2; influenza; miR-21; respiratory syncytial virus