Bmal1 integrates mitochondrial metabolism and macrophage activation

eLife

Alexander L Hyde¹  Sihao Liu²  Yae-Huei Liou²  Chuanrui Xu²  Nan-Shih Liao²  Ryan K Alexander²  Nelson H Knudsen²  Kyle A Starost²  David Jacobi²  Chih-Hao Lee³ 

[1]School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

[2]Department of Molecular Metabolism, Division of Biological Sciences, Harvard TH Chan School of Public Health, Boston, United States

[3]Institute of Molecular Biology, Academia Sinica, Taiwanese, China

关键词: macrophage;    energy metabolism;    anti-tumor activity;   

DOI  :  10.7554/eLife.54090

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown