Bmal1 integrates mitochondrial metabolism and macrophage activation

Area of Science:

• Immunology
• Metabolism
• Chronobiology

Background:

• Circadian rhythms regulate immune cell function and inflammatory processes.
• The role of the circadian clock in modulating immunometabolism is not well understood.
• Macrophages play critical roles in both inflammation and tumor immunity.

Purpose of the Study:

• To investigate the role of the molecular clock Bmal1 in regulating macrophage metabolism during inflammation.
• To determine if Bmal1 influences the tumor microenvironment and cancer progression.
• To explore potential therapeutic targets within the Bmal1-mediated metabolic pathway.

Main Methods:

• Utilized myeloid-specific Bmal1 knockout (M-BKO) mouse models.
• Stimulated macrophages with inflammatory agents like interferon-gamma/lipopolysaccharide (M1) and tumor-conditioned medium.
• Assessed mitochondrial function, reactive oxygen species production, and metabolic reprogramming.
• Analyzed tumor burden in melanoma models and tested the efficacy of SDH inhibitors.

Main Results:

• Bmal1 induction by inflammatory stimuli maintains mitochondrial metabolism in macrophages.
• M-BKO macrophages exhibit impaired mitochondrial function, increased ROS production, and Hif-1α-dependent metabolic reprogramming.
• Bmal1 deficiency in tumor-associated macrophages promotes an immunosuppressive tumor microenvironment, increasing melanoma burden.
• Administration of the SDH inhibitor dimethyl malonate suppressed tumor growth in M-BKO mice.

Conclusions:

• Bmal1 acts as a crucial metabolic checkpoint, integrating macrophage mitochondrial metabolism, redox balance, and immune effector functions.
• The Bmal1-Hif-1α regulatory loop is implicated in inflammatory diseases and cancer immunotherapy.
• Targeting the Bmal1-mediated metabolic pathway, specifically SDH, offers potential therapeutic strategies.