Imperial College London
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DrJamesPinkerton

Faculty of Medicine, National Heart & Lung Institute

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j.pinkerton

 
 
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G67Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kim:2016:10.1016/j.jaci.2016.04.038,
author = {Kim, RY and Horvat, JC and Pinkerton, JW and Starkey, MR and Essilfie, AT and Mayall, JR and Nair, PM and Hansbro, NG and Jones, B and Haw, TJ and Sunkara, KP and Nguyen, TH and Jarnicki, AG and Keely, S and Mattes, J and Adcock, IM and Foster, PS and Hansbro, PM},
doi = {10.1016/j.jaci.2016.04.038},
journal = {Journal of Allergy and Clinical Immunology},
pages = {519--532},
title = {MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2},
url = {http://dx.doi.org/10.1016/j.jaci.2016.04.038},
volume = {139},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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
AU  - Kim,RY
AU  - Horvat,JC
AU  - Pinkerton,JW
AU  - Starkey,MR
AU  - Essilfie,AT
AU  - Mayall,JR
AU  - Nair,PM
AU  - Hansbro,NG
AU  - Jones,B
AU  - Haw,TJ
AU  - Sunkara,KP
AU  - Nguyen,TH
AU  - Jarnicki,AG
AU  - Keely,S
AU  - Mattes,J
AU  - Adcock,IM
AU  - Foster,PS
AU  - Hansbro,PM
DO  - 10.1016/j.jaci.2016.04.038
EP  - 532
PY  - 2016///
SN  - 1097-6825
SP  - 519
TI  - MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2
T2  - Journal of Allergy and Clinical Immunology
UR  - http://dx.doi.org/10.1016/j.jaci.2016.04.038
UR  - http://hdl.handle.net/10044/1/39215
VL  - 139
ER  -
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