Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation

• Published in: Nature immunology Vol. 18; no. 10; pp. 1104 - 1116
• Main Authors: Park, Sung Ho, Kang, Kyuho, Giannopoulou, Eugenia, Qiao, Yu, Kang, Keunsoo, Kim, Geonho, Park-Min, Kyung-Hyun, Ivashkiv, Lionel B
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2017; Nature Publishing Group
• Subjects: 38/39; 45/15; 631/250; 631/250/127/1212; 631/250/127/1220; 631/250/2504/342; 631/250/256; Binding Sites; Biomedicine; Cell activation; Chromatin; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation; Cluster Analysis; Computational Biology - methods; Cytokines; Cytokines - genetics; Cytokines - metabolism; Epigenesis, Genetic; Epigenomics - methods; Gene Expression Profiling; Gene Expression Regulation; Gene silencing; Genetic aspects; Health aspects; High-Throughput Nucleotide Sequencing; Homeostasis; Humans; Immune response; Immunology; Infectious Diseases; Inflammation; Inflammation - etiology; Inflammation - metabolism; Interferon; Interferon Type I - metabolism; Lipopolysaccharides - immunology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Macrophages; Macrophages - immunology; Macrophages - metabolism; Monocytes - immunology; Monocytes - metabolism; Nucleotide Motifs; Promoter Regions, Genetic; Protein Binding; Protein Transport; Signal Transduction; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Toxicity; Transcription Factors - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.3818

No response by an immune cell occurs in isolation but is instead the summation of multiple interacting signals. Ivashkiv and colleagues describe the epigenetic landscape that results from the integration of the inflammatory cytokines type I interferons and TNF. Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-κB that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.