Immunity
Volume 51, Issue 2, 20 August 2019, Pages 241-257.e9
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Article
The Cytokine TNF Promotes Transcription Factor SREBP Activity and Binding to Inflammatory Genes to Activate Macrophages and Limit Tissue Repair

https://doi.org/10.1016/j.immuni.2019.06.005Get rights and content
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Highlights

  • TNF induces late-phase activation of SREBP2 and cholesterol genes in macrophages

  • SREBP2 binds and activates inflammatory target genes in TNF-stimulated macrophages

  • Inhibition of the TNF-SREBP axis promotes M2-like polarization and wound healing

  • The TNF-SREBP axis is an attractive therapeutic target for promoting tissue repair

Summary

Cytokine tumor necrosis factor (TNF)-mediated macrophage polarization is important for inflammatory disease pathogenesis, but the mechanisms regulating polarization are not clear. We performed transcriptomic and epigenomic analysis of the TNF response in primary human macrophages and revealed late-phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from an inflammatory to a reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a function and mechanism of action for SREBPs in augmenting TNF-induced macrophage activation and inflammation and open therapeutic avenues for promoting wound repair.

Keywords

TNF
SREBP2
macrophages
transcriptomics
epigenomics
cholesterol
wound healing
macrophage polarization
tissue repair
inflammation

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These authors contributed equally

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