The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis

Mariola Kurowska-Stolarska*, Manhl K. Hasoo, David J. Welsh, Lynn Stewart, Donna McIntyre, Brian E. Morton, Steven Johnstone, Ashley M. Miller, Darren L. Asquith, Neal L. Millar, Ann B. Millar, Carol A. Feghali-Bostwick, Nikhil Hirani, Peter J. Crick, Yuqin Wang, William J. Griffiths, Iain B. McInnes, Charles McSharry

*Corresponding author for this work

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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 We sought to determine the regulatory role of microRNA (miR)-155 in the profibrotic 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 profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and 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, TGF-β production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-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 profibrotic phenotype of IPF and miR-155−/− fibroblasts. Conclusions 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.
Original languageEnglish
Pages (from-to)1946-1956
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number6
Early online date14 Oct 2016
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • Animals
  • Bleomycin
  • Bronchoalveolar Lavage Fluid/cytology
  • Cell Count
  • Cells, Cultured
  • Collagen/metabolism
  • Fibroblasts/metabolism
  • Humans
  • Liver X Receptors/genetics
  • Lung/metabolism
  • Macrophages/metabolism
  • Mice, Knockout
  • MicroRNAs/genetics
  • Pulmonary Fibrosis/chemically induced

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    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., & McSharry, C. (2017). The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis. Journal of Allergy and Clinical Immunology, 139(6), 1946-1956. https://doi.org/10.1016/j.jaci.2016.09.021