Adam Collison1, Joerg Mattes, Maximilian Plank, Paul S Foster. 1. Experimental and Translational Respiratory Group, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Co-operative Research Centre for Asthma and Airways and Hunter Medical Research Institute, Callaghan, Australia.
Abstract
BACKGROUND: Glucocorticoids are used as mainstay therapy for asthma, but some patients remain resistant to therapy. MicroRNAs (miRNAs) are important regulators of the immune system by promoting the catabolism of their target transcripts as well as attenuating their translation. The role of miRNA in regulating allergic inflammation remains largely unknown. Blocking miRNA function may provide a new nonsteroidal anti-inflammatory approach to treatment. OBJECTIVES: To (1) determine the role of specific miRNAs in the regulation of hallmark features of allergic airways inflammation and (2) compare the efficacy of antagonizing miRNA function with that of steroid treatment. METHODS: Mice were sensitized and then aeroallergen-challenged with house dust mite to induce allergic airways disease, and alterations in the expression of miRNAs were characterized. Next mice were treated with antagomirs that inhibited the function of specific miRNAs in the lung or treated with dexamethasone and inflammatory lesions, and airway hyperresponsiveness was measured. RESULTS: miR-145, miR-21, and let-7b have been implicated in airway smooth muscle function, inflammation, and airways epithelial cell function, respectively. Inhibition of miR-145, but not miR-21 or lethal-7b, inhibited eosinophilic inflammation, mucus hypersecretion, T(H)2 cytokine production, and airway hyperresponsiveness. The anti-inflammatory effects of miR-145 antagonism were comparable to steroid treatment. CONCLUSION: Our study highlights the importance of understanding the contribution of miRNAs to pathogenesis of human allergic disease and their potential as novel anti-inflammatory targets.
BACKGROUND: Glucocorticoids are used as mainstay therapy for asthma, but some patients remain resistant to therapy. MicroRNAs (miRNAs) are important regulators of the immune system by promoting the catabolism of their target transcripts as well as attenuating their translation. The role of miRNA in regulating allergic inflammation remains largely unknown. Blocking miRNA function may provide a new nonsteroidal anti-inflammatory approach to treatment. OBJECTIVES: To (1) determine the role of specific miRNAs in the regulation of hallmark features of allergic airways inflammation and (2) compare the efficacy of antagonizing miRNA function with that of steroid treatment. METHODS:Mice were sensitized and then aeroallergen-challenged with house dust mite to induce allergic airways disease, and alterations in the expression of miRNAs were characterized. Next mice were treated with antagomirs that inhibited the function of specific miRNAs in the lung or treated with dexamethasone and inflammatory lesions, and airway hyperresponsiveness was measured. RESULTS:miR-145, miR-21, and let-7b have been implicated in airway smooth muscle function, inflammation, and airways epithelial cell function, respectively. Inhibition of miR-145, but not miR-21 or lethal-7b, inhibited eosinophilic inflammation, mucus hypersecretion, T(H)2 cytokine production, and airway hyperresponsiveness. The anti-inflammatory effects of miR-145 antagonism were comparable to steroid treatment. CONCLUSION: Our study highlights the importance of understanding the contribution of miRNAs to pathogenesis of humanallergic disease and their potential as novel anti-inflammatory targets.