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Autoimmunity, Inflammatory bowel disease, and cancer

IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo

Mucosal Immunology volume 11, pages 871880 (2018) | Download Citation

Abstract

Colonic macrophages induce pathogenic inflammation against commensal bacteria, leading to inflammatory bowel disease (IBD). Although the ontogeny of colonic macrophages has been well studied in the past decade, how macrophages gain colitogenic properties during the development of colitis is unknown. Using a chemically induced colitis model, we showed that accumulated Ly6C+ cells consisting of inflammatory monocytes and inflammatory macrophages strongly expressed representative colitogenic mediators such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). The interferon-γ–signal transducer and activator of transcription 1 (IFN-γ–Stat1) pathway was required for generating colitogenic macrophages, given that Stat1−/− mice had less severe colitis and fewer colitogenic macrophages. Notably, IFN-γ induced histone acetylation at the promoter regions of the Tnf and Nos2 loci in the monocyte and macrophage lineage, indicating that IFN-γ-dependent epigenetic regulation instructs the development of the colitogenic monocyte and macrophage lineage in vivo. Collectively, our results provide the essential mechanism by which dysregulated colitogenic monocytes/macrophages develop at the colon mucosa during inflammation, and suggest a new drug target for treating IBD.

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Acknowledgements

We thank H. Kamioka for secretarial support and A. Hosono and M. Tsuda for technical support. This work was supported by the Tuchiya Memorial Foundation (to Y.N.), a Grant-in-Aid for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to T.O.), and the Joint Usage/Research Program of the Medical Research Institute, Tokyo Medical and Dental University (to K.T.).

Author information

Affiliations

  1. Department of Biodefense Research, Tokyo Medical and Dental University, Tokyo, Japan

    • Y Nakanishi
    • , T Sato
    •  & T Ohteki
  2. IBD project, Laboratory for Integrated Research Projects on Intractable Diseases, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    • Y Nakanishi
  3. Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama, Japan

    • T Sato
  4. College of Bioresource Sciences, Nihon University, Kanagawa, Japan

    • K Takahashi

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Competing interests

The authors declared no conflict of interest.

Corresponding author

Correspondence to T Ohteki.

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DOI

https://doi.org/10.1038/mi.2017.104

Author contributions

Y.N. designed and conducted the experiments, T.S. and K.T. assisted with some experiments, and Y.N. and T.O. analyzed data and prepared the manuscript.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/mi