Immunity
Volume 48, Issue 1, 16 January 2018, Pages 75-90.e6
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Article
The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages

https://doi.org/10.1016/j.immuni.2017.12.010Get rights and content
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Highlights

  • IL-4-activated STAT6 acts as a transcriptional repressor in macrophages

  • IL-4-STAT6-repressed enhancers associate with reduced LDTF and p300 binding

  • Inflammatory responsiveness of the IL-4-repressed enhancers is attenuated

  • IL-4 limits the LPS-induced inflammasome activation, IL-1β production, and pyroptosis

Summary

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

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15

These authors contributed equally

16

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