IFN-γ Selectively Suppresses a Subset of TLR4-activated Genes and Enhancers to Potentiate Macrophage Activation

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jul 27

PMID 31346169

Citations 54

Authors

Kyuho Kang

Mahesh Bachu

Sung Ho Park

Keunsoo Kang

Seyeon Bae

Kyung-Hyun Park-Min

Lionel B Ivashkiv

Affiliations

Soon will be listed here.

Abstract

Activation of macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-γ and LPS via synergistic induction of canonical, inflammatory NF-κB target genes. However, whether IFN-γ negatively regulates components of the LPS response, and how this may affect macrophage activation, is still unclear. Here we use combined transcriptomic and epigenomic approaches to find that IFN-γ selectively abrogates LPS-induced feedback and alters macrophage metabolic pathways by suppressing TLR4-mediated gene activation. In contrast to superinduction of inflammatory genes via enhancers that bind IRF1 and STAT1, IFN-γ represses target enhancers that bind STAT3. TLR4-activated but IFN-γ-suppressed enhancers comprise two subsets discernable by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin. Our findings thus show that IFN-γ suppresses feedback inhibitory and metabolic components of TLR responses to enhance macrophage activation; they also provide insights for IFN-γ-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.

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References

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Lam M, Li W, Rosenfeld M, Glass C . Enhancer RNAs and regulated transcriptional programs. Trends Biochem Sci. 2014; 39(4):170-82. PMC: 4266492. DOI: 10.1016/j.tibs.2014.02.007. View

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

Ip W, Hoshi N, Shouval D, Snapper S, Medzhitov R . Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017; 356(6337):513-519. PMC: 6260791. DOI: 10.1126/science.aal3535. View

Phan A, Goldrath A, Glass C . Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity. Immunity. 2017; 46(5):714-729. PMC: 5505665. DOI: 10.1016/j.immuni.2017.04.016. View

Ginhoux F, Schultze J, Murray P, Ochando J, Biswas S . New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol. 2015; 17(1):34-40. DOI: 10.1038/ni.3324. View

Hutchins A, Poulain S, Miranda-Saavedra D . Genome-wide analysis of STAT3 binding in vivo predicts effectors of the anti-inflammatory response in macrophages. Blood. 2012; 119(13):e110-9. DOI: 10.1182/blood-2011-09-381483. View

Hu X, Chen J, Wang L, Ivashkiv L . Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol. 2007; 82(2):237-43. DOI: 10.1189/jlb.1206763. View

Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M . Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014; 159(6):1312-26. PMC: 4437213. DOI: 10.1016/j.cell.2014.11.018. View

10.

Chiche L, Jourde-Chiche N, Whalen E, Presnell S, Gersuk V, Dang K . Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol. 2014; 66(6):1583-95. PMC: 4157826. DOI: 10.1002/art.38628. View

11.

Allen B, Taatjes D . The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol. 2015; 16(3):155-66. PMC: 4963239. DOI: 10.1038/nrm3951. View

12.

Czimmerer Z, Daniel B, Horvath A, Ruckerl D, Nagy G, Kiss M . The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages. Immunity. 2018; 48(1):75-90.e6. PMC: 5772169. DOI: 10.1016/j.immuni.2017.12.010. View

13.

Su X, Yu Y, Zhong Y, Giannopoulou E, Hu X, Liu H . Interferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat Immunol. 2015; 16(8):838-849. PMC: 4509841. DOI: 10.1038/ni.3205. View

14.

Netea M, Joosten L, Latz E, Mills K, Natoli G, Stunnenberg H . Trained immunity: A program of innate immune memory in health and disease. Science. 2016; 352(6284):aaf1098. PMC: 5087274. DOI: 10.1126/science.aaf1098. View

15.

Kaikkonen M, Spann N, Heinz S, Romanoski C, Allison K, Stender J . Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013; 51(3):310-25. PMC: 3779836. DOI: 10.1016/j.molcel.2013.07.010. View

16.

McCarthy D, Chen Y, Smyth G . Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012; 40(10):4288-97. PMC: 3378882. DOI: 10.1093/nar/gks042. View

17.

Li W, Notani D, Rosenfeld M . Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet. 2016; 17(4):207-23. DOI: 10.1038/nrg.2016.4. View

18.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

19.

Kagey M, Newman J, Bilodeau S, Zhan Y, Orlando D, van Berkum N . Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010; 467(7314):430-5. PMC: 2953795. DOI: 10.1038/nature09380. View

20.

Piccolo V, Curina A, Genua M, Ghisletti S, Simonatto M, Sabo A . Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk. Nat Immunol. 2017; 18(5):530-540. PMC: 5524187. DOI: 10.1038/ni.3710. View