Bmal1 is known as the master clock gene as its deletion completely ablates all rhythmic activity throughout the organism ( 3). At the molecular level, these rhythms are generated by a series of interlocking transcription-translation feedback loops (TTFL) centred around the core clock component BMAL1 ( 2). The SCN integrates light signals which synchronize the central clock to the external environment. Circadian rhythms are oscillations in behaviour and physiology with a 24-hour periodicity and are directed by the central master clock which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus ( 1). This rotation necessitated the evolution of the circadian clock, which allows organisms to anticipate and respond to these predictable environmental changes. Life on Earth follows a predictable daily rhythm, dictated by the planet’s daily rotation on its axis. These data provide insight into the control of macrophage driven inflammation by the molecular clock, and the potential for time-based therapeutics against a range of chronic inflammatory diseases. Overall, this work demonstrates that BMAL1 is a key metabolic sensor in macrophages, and its deficiency leads to a metabolic shift of enhanced glycolysis and mitochondrial respiration, leading to a heightened pro-inflammatory state. We further demonstrate that BMAL1 modulates the level and localisation of the glycolytic enzyme PKM2, which in turn activates STAT3 to further drive Il-1β mRNA expression. We now describe that the macrophage molecular clock, through Bmal1, regulates the uptake of glucose, its flux through glycolysis and the Krebs cycle, including the production of the metabolite succinate to drive Il-1β production. Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1β. Intracellular metabolic pathways direct the macrophage inflammatory response, however whether the clock is impacting intracellular metabolism to direct this response is unclear. The transcription factor BMAL1 is a clock protein that generates daily or circadian rhythms in physiological functions including the inflammatory response of macrophages. 5Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom.4Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.3Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.2School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin, Ireland. 1School of Pharmacy and Biomolecular Sciences and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin, Ireland.
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