Bmal1 integrates mitochondrial metabolism and macrophage activation
- HSPH, United States
- Academia Sinica, Taiwan, Republic of China
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.
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RNA-sequencing of Wild-type and Bmal1 KO M1 macrophagesNCBI Gene Expression Omnibus, GSE148510.
Article and author information
Author details
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.
Ethics
Animal experimentation: All animal studies were approved by the Harvard Medical Area Standing Committee on Animal Research. IACUC protocol #IS00001011
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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