Kurowska-Stolarska, M. et al. (2017) The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis. Journal of Allergy and Clinical Immunology, 139(6), pp. 1946-1956. (doi: 10.1016/j.jaci.2016.09.021) (PMID:27746237) (PMCID:PMC5457127)
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130658.pdf - Published Version Available under License Creative Commons Attribution. 2MB |
Abstract
Background: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways. Objectives: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis. Methods: Bleomycin-induced lung fibrosis in wild-type and miR-155-/- mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. Results: miR-155-/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155-/- fibroblasts. Conclusion: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | McInnes, Professor Iain and Johnstone, Dr Steven and Miller, Dr Ashley and Stewart, Ms Lynn and Welsh, Dr David and McIntyre, Dr Donna and Kurowska-Stolarska, Dr Mariola and McSharry, Dr Charles |
| Authors: | Kurowska-Stolarska, M., Hasoo, M. K., Welsh, D. J., Stewart, L., McIntyre, D., Morton, B. E., Johnstone, S., Miller, A. M., Asquith, D. L., Millar, N. L., Millar, A. B., Feghali-Bostwick, C. A., Hirani, N., Crick, P. J., Wang, Y., Griffiths, W. J., McInnes, I. B., and McSharry, C. |
| College/School: | College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences |
| Journal Name: | Journal of Allergy and Clinical Immunology |
| Publisher: | Elsevier |
| ISSN: | 0091-6749 |
| ISSN (Online): | 1097-6825 |
| Published Online: | 14 October 2016 |
| Copyright Holders: | Copyright © 2016 The Authors |
| First Published: | First published in Journal of Allergy and Clinical Immunology 139(6):1946-1956 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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