Abstract

Metabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-g/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1a-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1a activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1a regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

Data availability

Raw RNA-seq data submitted to GEO: accession number GSE148510. All analyzed RNA-seq and metabolite data are included in the manuscript and source data for Fig 3 and Fig. 5.

The following data sets were generated

Article and author information

Author details

  1. Ryan K Alexander

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yae-Huei Liou

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nelson H Knudsen

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kyle A Starost

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Chuanrui Xu

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3225-4083
  6. Alexander L Hyde

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sihao Liu

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. David Jacobi

    Department of Molecular Metabolism, HSPH, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nan-Shih Liao

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  10. Chih-Hao Lee

    Department of Molecular Metabolism, HSPH, Boston, United States
    For correspondence
    clee@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6090-0786

Funding

National Institute of Allergy and Infectious Diseases (R21AI131659)

  • Chih-Hao Lee

National Institute of General Medical Sciences (F31GM117854)

  • Ryan K Alexander

National Institute of Diabetes and Digestive and Kidney Diseases (F31DK107256)

  • Nelson H Knudsen

Ministry of Science and Technology, Taiwan, ROC

  • Yae-Huei Liou

Academia Sinica (AS-106-TP-L08)

  • Nan-Shih Liao

American Heart Association (16GRNT31460005)

  • Chih-Hao Lee

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113791)

  • Chih-Hao Lee

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Carla V Rothlin, Yale School of Medicine, United States

Ethics

Animal experimentation: All animal studies were approved by the Harvard Medical Area Standing Committee on Animal Research. IACUC protocol #IS00001011

Version history

  1. Received: December 2, 2019
  2. Accepted: May 11, 2020
  3. Accepted Manuscript published: May 12, 2020 (version 1)
  4. Version of Record published: May 29, 2020 (version 2)

Copyright

© 2020, Alexander et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ryan K Alexander
  2. Yae-Huei Liou
  3. Nelson H Knudsen
  4. Kyle A Starost
  5. Chuanrui Xu
  6. Alexander L Hyde
  7. Sihao Liu
  8. David Jacobi
  9. Nan-Shih Liao
  10. Chih-Hao Lee
(2020)
Bmal1 integrates mitochondrial metabolism and macrophage activation
eLife 9:e54090.
https://doi.org/10.7554/eLife.54090

Share this article

https://doi.org/10.7554/eLife.54090

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