miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program

Nat Commun. 2015 Oct 5;6:8523. doi: 10.1038/ncomms9523.

Abstract

Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARγ, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Down-Regulation
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Gene Expression Regulation
  • Humans
  • Interleukin-13 / immunology*
  • Interleukin-4 / immunology*
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / immunology*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • PPAR gamma / metabolism
  • Phosphorylation
  • Pinocytosis
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / immunology*
  • Real-Time Polymerase Chain Reaction
  • STAT6 Transcription Factor / metabolism
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Up-Regulation

Substances

  • Interleukin-13
  • MIRN130 microRNA, human
  • MIRN130 microRNA, mouse
  • MIRN142 microRNA, human
  • MicroRNAs
  • Mirn142 microRNA, mouse
  • PPAR gamma
  • SOCS1 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Interleukin-4