Letter | Published:

Identification of an atypical monocyte and committed progenitor involved in fibrosis

Nature volume 541, pages 96101 (05 January 2017) | Download Citation

Abstract

Monocytes and macrophages comprise a variety of subsets with diverse functions1,2,3,4,5. It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages6,7,8. However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1+Msr1+Ly6CF4/80Mac1+ monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein β (C/EBPβ), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb−/− haematopoietic cells. Adoptive transfer of SatM into Cebpb−/− mice resulted in fibrosis. Notably, SatM are derived from Ly6CFcεRI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6CFcεRI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBPβ licenses differentiation of SatM from their committed progenitor.

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Acknowledgements

We thank S. Saeki, S. Watanabe, R. Takenaka and M. Miyamoto for assistance with experiments, and T. Matsuki, T. Kawasaki, H. Kanemaru, H. Tanaka and K. Kuniyoshi for helpful discussions. We thank T. Kitamura for providing PlatE cells. We also thank E. Kamada for secretarial assistance, and C. Funamoto, N. Kitagaki, A. Wataki, K. Yokoyama and R. Kawaguchi for technical assistance. This work was supported by the Government of Japan and the Japan Society for the Promotion of Science (JSPS) through the funding program for World-Leading Innovative R&D on Science and Technology (FIRST Program), by Japan Science and Technology Agency (JST) thorough funding for a Grant-in-Aid for Young Scientists (A)(16H06234), Specially Promoted Research (15H05704) and the US National Institutes of Health (P01-AI070167) and ‘Visionary Research Fund’ from Takeda Science Foundation. A part of this work was supported by the Nanotechnology Platform (project number 12024046) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

Author information

Author notes

    • Takashi Satoh
    •  & Katsuhiro Nakagawa

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan

    • Takashi Satoh
    • , Katsuhiro Nakagawa
    • , Fumihiro Yamane
    • , Kiyoharu Fukushima
    • , Isao Ebina
    •  & Shizuo Akira
  2. Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan

    • Takashi Satoh
    • , Katsuhiro Nakagawa
    • , Fumihiro Yamane
    • , Kiyoharu Fukushima
    • , Isao Ebina
    •  & Shizuo Akira
  3. Laboratory of Biofunctional Imaging, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan

    • Fuminori Sugihara
    •  & Yoshichika Yoshioka
  4. Research Center for Ultra-high Voltage Electron Microscopy, Osaka University, Osaka, 567-0047, Japan

    • Ryusuke Kuwahara
  5. Discovery Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kanagawa, 247-8530, Japan

    • Motooki Ashihara
    • , Yosuke Minowa
    •  & Isao Ebina
  6. Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan

    • Atsushi Kumanogoh
  7. Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan

    • Atsushi Kumanogoh

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Contributions

T.S. designed and performed the experiments and wrote the manuscript. K.F., I.E., F.Y. and A.K. helped with experiments. K.N. performed the experiments. M.A. and Y.M. performed bioinformatics analysis. F.S. and Y.Y. performed the MRI analysis. R.K. performed the electron microscopy analysis. S.A. wrote the manuscript and supervised the project.

Competing interests

S.A. has research support from Chugai Pharmaceutical Co., Ltd. The terms of this arrangement have been reviewed and approved by the Osaka University in accordance with its policy on objectivity in research.

Corresponding author

Correspondence to Shizuo Akira.

Reviewer Information Nature thanks I. Amit, D. Brenner, F. Geissmann and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Videos

  1. 1.

    Spatio−temporal analysis of lung by MRI

    The animation shows lung of WT chimeric in normal condition.The images were taken by MRI at day 0.

  2. 2.

    Spatio−temporal analysis of BLM induced inflammation by MRI

    The animation shows inflamed area (red) in lung of WT chimeric. The images were taken by MRI after 4 days BLM administration.

  3. 3.

    Spatio−temporal analysis of BLM induced inflammation by MRI

    The animation shows inflamed area (red) in lung of C/ebpb–/– chimeric mice. The images were taken by MRI after 4 days BLM administration.

  4. 4.

    Spatio−temporal analysis of BLM induced fibrosis by MRI

    The animation shows fibrotic area (blue) in lung of WT chimeric mice. The images were taken by MRI after 14 days BLM administration.

  5. 5.

    Spatio−temporal analysis of BLM induced fibrosis by MRI

    The animation shows fibrotic area (blue) in lung of C/ebpb–/– chimeric mice. The images were taken by MRI after 14 days BLM administration.

  6. 6.

    Three−dimensional tomographic imaging of SatM in BM by STEM

    SatM was sorted from BM, and the Image was taken by STEM.

  7. 7.

    Three−dimensional tomographic imaging of SMP in BM by STEM

    SMP was sorted from BM, and the Image was taken by STEM.

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DOI

https://doi.org/10.1038/nature20611

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