Abstract
BackgroundIdiopathic 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.ObjectivesWe 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.MethodsBleomycin-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.ResultsmiR-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.ConclusionsWe 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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal
We showed previously that miR-1552/2 mice have higher serum cholesterol concentrations while on a high fat diet[22]; to test whether different oxysterol concentrations in miR-1552/2 mice treated with bleomycin were responsible for the Lxra activation and exacerbated lung fibrosis, we profiled serum oxysterols using mass spectrometry (Table E3)
Because constitutively increased LXRa expression (Fig 5, A) and activity contributed to IPF fibroblast phenotype, we investigated whether this was caused by altered serum concentrations of LXRa oxysterol ligands in patients with IPF or by altered miR-155 expression
Summary
Idiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal. Epigenetic changes contribute to IPF; microRNAs may reveal novel pathogenic pathways. Oxysterol measurement was supported by Biotechnology & Biological Sciences Research Council
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