title: MicroRNA Expression Is Altered in an Ovalbumin-Induced Asthma Model and Targeting miR-155 with Antagomirs Reveals Cellular Specificity.
abstract: MicroRNAs are post-transcriptional regulators of gene expression that are differentially regulated during development and in inflammatory diseases. A role for miRNAs in allergic asthma is emerging and further investigation is required to determine whether they may serve as potential therapeutic targets. We profiled miRNA expression in murine lungs from an ovalbumin-induced allergic airways disease model, and compared expression to animals receiving dexamethasone treatment and non-allergic controls. Our analysis identified 29 miRNAs that were significantly altered during allergic inflammation. Target prediction analysis revealed novel genes with altered expression in allergic airways disease and suggests synergistic miRNA regulation of target mRNAs. To assess the impacts of one induced miRNA on pathology, we targeted miR-155-5p using a specific antagomir. Antagomir administration successfully reduced miR-155-5p expression with high specificity, but failed to alter the disease phenotype. Interestingly, further investigation revealed that antagomir delivery has variable efficacy across different immune cell types, effectively targeting myeloid cell populations, but exhibiting poor uptake in lymphocytes. Our findings demonstrate that antagomir-based targeting of miRNA function in the lung is highly specific, but highlights cell-specificity as a key limitation to be considered for antagomir-based strategies as therapeutics.
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Maximilian W
authors.initials: MW
authors.lastname: Plank
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Maltby
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Hock L
authors.initials: HL
authors.lastname: Tay
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Eyers
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Centre for Asthma and Respiratory Diseases, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D003907:Dexamethasone / Q000009:adverse effects*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000494:pharmacology; D009928:Organ Specificity; D010047:Ovalbumin / Q000009:adverse effects*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D009841:Oligonucleotides; D003907:Dexamethasone; D010047:Ovalbumin