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Publication

Bmal1 integrates mitochondrial metabolism and macrophage activation.

eLife | 2020

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under 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 production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

Pubmed ID: 32396064 RIS Download

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Associated grants

Agency: NIGMS NIH HHS, United States
Id: F31 GM117854
Agency: NIDDK NIH HHS, United States
Id: F31 DK107256
Agency: NIAID NIH HHS, United States
Id: R21 AI131659
Agency: NIDDK NIH HHS, United States
Id: R01 DK064750
Agency: NIEHS NIH HHS, United States
Id: T32 ES016645
Agency: American Heart Association, International
Id: 16GRNT31460005
Agency: Academia Sinica, International
Id: AS-106-TP-L08
Agency: NIDDK NIH HHS, United States
Id: R01 DK113791

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RRID:SCR_001672

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