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.
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.
Authors: Alan C-Y Hsu; Kamal Dua; Malcolm R Starkey; Tatt-Jhong Haw; Prema M Nair; Kristy Nichol; Nathan Zammit; Shane T Grey; Katherine J Baines; Paul S Foster; Philip M Hansbro; Peter A Wark Journal: JCI Insight Date: 2017-04-06
Authors: Malcolm R Starkey; Maximilian W Plank; Paolo Casolari; Alberto Papi; Stelios Pavlidis; Yike Guo; Guy J M Cameron; Tatt Jhong Haw; Anthony Tam; Ma'en Obiedat; Chantal Donovan; Nicole G Hansbro; Duc H Nguyen; Prema Mono Nair; Richard Y Kim; Jay C Horvat; Gerard E Kaiko; Scott K Durum; Peter A Wark; Don D Sin; Gaetano Caramori; Ian M Adcock; Paul S Foster; Philip M Hansbro Journal: Eur Respir J Date: 2019-07-18 Impact factor: 16.671
Authors: Jose L Gomez; Ailu Chen; Maria Paula Diaz; Nicholas Zirn; Amolika Gupta; Clemente Britto; Maor Sauler; Xiting Yan; Emma Stewart; Kyle Santerian; Nicole Grant; Qing Liu; Rebecca Fry; Julia Rager; Lauren Cohn; Neil Alexis; Geoffrey L Chupp Journal: Am J Respir Crit Care Med Date: 2020-07-01 Impact factor: 21.405
Authors: Gang Liu; Marion A Cooley; Andrew G Jarnicki; Theo Borghuis; Prema M Nair; Gavin Tjin; Alan C Hsu; Tatt Jhong Haw; Michael Fricker; Celeste L Harrison; Bernadette Jones; Nicole G Hansbro; Peter A Wark; Jay C Horvat; W Scott Argraves; Brian G Oliver; Darryl A Knight; Janette K Burgess; Philip M Hansbro Journal: JCI Insight Date: 2019-07-25
Authors: Lingyin Ge; David M Habiel; Phil M Hansbro; Richard Y Kim; Sina A Gharib; Jeffery D Edelman; Melanie Königshoff; Tanyalak Parimon; Rena Brauer; Ying Huang; Jenieke Allen; Dianhua Jiang; Adrianne A Kurkciyan; Takako Mizuno; Barry R Stripp; Paul W Noble; Cory M Hogaboam; Peter Chen Journal: JCI Insight Date: 2016-12-08