title: The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom. Electronic address: Mariola.Kurowska-Stolarska@glasgow.ac.uk.
authors.forename: Mariola
authors.initials: M
authors.lastname: Kurowska-Stolarska
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Manhl K
authors.initials: MK
authors.lastname: Hasoo
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Welsh
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Lynn
authors.initials: L
authors.lastname: Stewart
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Donna
authors.initials: D
authors.lastname: McIntyre
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Morton
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Johnstone
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Miller
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Asquith
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Millar
authors.affiliation: Academic Respiratory Unit, Learning and Research, University of Bristol, Bristol, United Kingdom.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Millar
authors.affiliation: Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.affiliation: University of Edinburgh/MRC Centre for Inflammation Research, the Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hirani
authors.affiliation: College of Medicine, Swansea University, Swansea, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crick
authors.affiliation: College of Medicine, Swansea University, Swansea, United Kingdom.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Medicine, Swansea University, Swansea, United Kingdom.
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; Greater Glasgow and Clyde Clinical Research and Development, Yorkhill Hospital, Glasgow, United Kingdom. Electronic address: Charles.McSharry@glasgow.ac.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: McSharry
mesh_terms: D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D001761:Bleomycin; D003094:Collagen
keywords: MicroRNA-155; alternatively activated macrophages; fibroblasts; liver X receptor; lung fibrosis