Abstract
The transcription factor BMAL1 is a clock protein that generates daily or circadian rhythms in physiological functions including the inflammatory response of macrophages. Intracellular metabolic pathways direct the macrophage inflammatory response, however whether the clock is impacting intracellular metabolism to direct this response is unclear. Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1β. 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. 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. 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. 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.
Highlights
Life on Earth follows a predictable daily rhythm, dictated by the planet’s daily rotation on its axis
bone marrow derived macrophages (BMDMs) were prepared from Bmal1wt/wtLys-MCre (i.e. Bmal1+/+) and Bmal1LoxP/LoxPLyz-MCre (i.e. Bmal1-/-) mice that have Bmal1 excised in myeloid lineage cells
Bmal1-/- BMDMs demonstrated higher oxygen consumption rate (OCR) basally and following 4 hours of LPS stimulation but no differences were evident after 24 hours of LPS, in line with the typical kinetics of Warburg metabolism in macrophages [26, 54] (Figure 1A)
Summary
Life on Earth follows a predictable daily rhythm, dictated by the planet’s daily rotation on its axis. This rotation necessitated the evolution of the circadian clock, which allows organisms to anticipate and respond to these predictable environmental changes. BMAL1 and its heterodimerization partner CLOCK bind Ebox sites in promoters of clock-controlled genes across the genome. This heterodimer can induce transcription of the negative arms of the molecular clock which feedback and disrupt the BMAL1-CLOCK heterodimer, driving precise 24 hourrhythms of clock-controlled genes. The SCN clock maintains the synchrony of peripheral clocks, throughout the body via rhythmic endocrine and autonomic signalling [4, 5]. The immune system is highly rhythmic, via a network of SCNdriven systemic signals which impact immune cells and endogenous clocks within those immune cells
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