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Nat Immunol. 2017 May;18(5):530-540. doi: 10.1038/ni.3710. Epub 2017 Mar 13.

Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk.

Author information

1
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
2
San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
3
Humanitas Clinical and Research Center, Milan, Italy.
4
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
5
Department of Biomedical Sciences, School of Medicine, Humanitas University, Milan, Italy.

Abstract

Stimulation of macrophages with interferon-γ (IFN-γ) and interleukin 4 (IL-4) triggers distinct and opposing activation programs. During mixed infections or cancer, macrophages are often exposed to both cytokines, but how these two programs influence each other remains unclear. We found that IFN-γ and IL-4 mutually inhibited the epigenomic and transcriptional changes induced by each cytokine alone. Computational and functional analyses revealed the genomic bases for gene-specific cross-repression. For instance, while binding motifs for the transcription factors STAT1 and IRF1 were associated with robust and IL-4-resistant responses to IFN-γ, their coexistence with binding sites for auxiliary transcription factors such as AP-1 generated vulnerability to IL-4-mediated inhibition. These data provide a core mechanistic framework for the integration of signals that control macrophage activation in complex environmental conditions.

PMID:
28288101
PMCID:
PMC5524187
DOI:
10.1038/ni.3710
[Indexed for MEDLINE]
Free PMC Article

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