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

Kim, RY; Horvat, JC; Pinkerton, JW; Starkey, MR; Essilfie, AT; Mayall, JR; Nair, PM; Hansbro, NG; Jones, B; Haw, TJ; Sunkara, KP; Nguyen, TH; Jarnicki, AG; Keely, S; Mattes, J; Adcock, IM; Foster, PS; Hansbro, PM

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

Horvat, JC Pinkerton, JW Starkey, MR Essilfie, AT Mayall, JR Nair, PM Hansbro, NG Jones, B Haw, TJ Sunkara, KP Nguyen, TH Jarnicki, AG Keely, S Mattes, J Adcock, IM Foster, PS Hansbro, PM

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Publication Type:: Journal Article
Citation:: Journal of Allergy and Clinical Immunology, 2017, 139 (2), pp. 519 - 532
Issue Date:: 2017-02-01

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Field	Value	Language
dc.contributor.author	Kim, RY https://orcid.org/0000-0002-8709-5270	en_US
dc.contributor.author	Horvat, JC	en_US
dc.contributor.author	Pinkerton, JW	en_US
dc.contributor.author	Starkey, MR	en_US
dc.contributor.author	Essilfie, AT	en_US
dc.contributor.author	Mayall, JR	en_US
dc.contributor.author	Nair, PM	en_US
dc.contributor.author	Hansbro, NG	en_US
dc.contributor.author	Jones, B	en_US
dc.contributor.author	Haw, TJ	en_US
dc.contributor.author	Sunkara, KP	en_US
dc.contributor.author	Nguyen, TH	en_US
dc.contributor.author	Jarnicki, AG	en_US
dc.contributor.author	Keely, S	en_US
dc.contributor.author	Mattes, J	en_US
dc.contributor.author	Adcock, IM	en_US
dc.contributor.author	Foster, PS	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.date.available	2016-04-29	en_US
dc.date.issued	2017-02-01	en_US
dc.identifier.citation	Journal of Allergy and Clinical Immunology, 2017, 139 (2), pp. 519 - 532	en_US
dc.identifier.issn	0091-6749	en_US
dc.identifier.uri	http://hdl.handle.net/10453/126241
dc.description.abstract	© 2016 American Academy of Allergy, Asthma & Immunology 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.	en_US
dc.relation.ispartof	Journal of Allergy and Clinical Immunology	en_US
dc.relation.isbasedon	10.1016/j.jaci.2016.04.038	en_US
dc.subject.classification	Allergy	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred BALB C	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Chlamydia muridarum	en_US
dc.subject.mesh	Haemophilus influenzae	en_US
dc.subject.mesh	Respiratory Syncytial Viruses	en_US
dc.subject.mesh	Respiratory Tract Infections	en_US
dc.subject.mesh	Asthma	en_US
dc.subject.mesh	Pneumonia	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Dexamethasone	en_US
dc.subject.mesh	MicroRNAs	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Phosphorylation	en_US
dc.subject.mesh	Drug Resistance	en_US
dc.subject.mesh	Proto-Oncogene Proteins c-akt	en_US
dc.subject.mesh	PTEN Phosphohydrolase	en_US
dc.subject.mesh	Influenza A Virus, H1N1 Subtype	en_US
dc.subject.mesh	Histone Deacetylase 2	en_US
dc.subject.mesh	Phosphatidylinositol 3-Kinases	en_US
dc.subject.mesh	Antagomirs	en_US
dc.title	MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	139	en_US
utslib.for	1107 Immunology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Graduate School of Health
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	139	en_US

Abstract:

© 2016 American Academy of Allergy, Asthma & Immunology 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.

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http://hdl.handle.net/10453/126241