The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages

Immunity. 2018 Jan 16;48(1):75-90.e6. doi: 10.1016/j.immuni.2017.12.010.


The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli.

Keywords: IL-1β; IL-4; STAT6; alternative macrophage polarization; inflammasome activation; inflammation; macrophage epigenomics; pyroptosis; repression; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Enhancer Elements, Genetic
  • Flow Cytometry
  • Gene Expression Regulation
  • Inflammasomes / metabolism
  • Interleukin-4 / metabolism*
  • Laser Scanning Cytometry
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism*
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Polymerase Chain Reaction
  • Pyroptosis / genetics
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Inflammasomes
  • Lipopolysaccharides
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4