Researchers from Kyushu University have discovered a previously unknown mechanism by which the circadian clock protein BMAL1 enhances inflammatory responses in the immune system. The findings were published in the journal Cell Reports.
Circadian rhythms—the body's internal biological clock—regulate numerous physiological processes, including sleep, metabolism, hormone production, and immune function. The new study shows that these rhythms directly influence the behavior of macrophages, key immune cells involved in inflammation and tissue repair.
Macrophages can adopt two main functional states. The M1 state promotes inflammation and helps fight infections, while the M2 state supports tissue repair and the resolution of inflammation. Maintaining a balance between these states is crucial, as disruptions have been linked to chronic inflammatory diseases, diabetes, liver disorders, and cancer.
The researchers found that BMAL1 plays a central role in pushing macrophages toward the pro-inflammatory M1 state. Experiments in mice demonstrated that removing BMAL1 from macrophages reduced inflammation and suppressed the development of liver tumors following exposure to the chemical carcinogen diethylnitrosamine.
To investigate the underlying mechanism, the scientists performed a proteomic analysis and discovered that BMAL1 interacts with MFP2, an enzyme involved in fatty acid oxidation.
Under normal conditions, MFP2 moves into the cell nucleus, where it increases levels of acetyl-CoA and promotes protein acetylation, including that of NF-κB (p65), a major regulator of inflammatory genes.
Activation of NF-κB triggers the expression of inflammatory genes and drives macrophages into the M1 inflammatory state. Importantly, the amount of MFP2 present in the nucleus fluctuates throughout the day according to circadian rhythms controlled by BMAL1. In mice lacking BMAL1, this daily rhythm disappeared.
The findings suggest that the biological clock does more than simply set the timing of immune responses—it actively regulates the intensity of inflammation through metabolic processes occurring within the cell nucleus.
According to the authors, the discovery could have important therapeutic implications. Future treatments for inflammatory diseases and cancer may involve targeting MFP2 directly or optimizing the timing of medication administration to align with the body's natural circadian rhythms.
The study adds to growing evidence that when treatments are given may be nearly as important as what treatments are given, opening new possibilities in the emerging field of chronomedicine.
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