The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β

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 intracellula...

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Autores principales:	George A. Timmons, Richard G. Carroll, James R. O’Siorain, Mariana P. Cervantes-Silva, Lauren E. Fagan, Shannon L. Cox, Eva Palsson-McDermott, David K. Finlay, Emma E. Vincent, Nicholas Jones, Annie M. Curtis
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	macrophage inflammation metabolism molecular clock IL-1β pSTAT3 Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/8e053272114849dda92fb87d549b098f
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spelling	oai:doaj.org-article:8e053272114849dda92fb87d549b098f2021-11-09T06:35:22ZThe Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β1664-322410.3389/fimmu.2021.700431https://doaj.org/article/8e053272114849dda92fb87d549b098f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.700431/fullhttps://doaj.org/toc/1664-3224The 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.George A. TimmonsRichard G. CarrollJames R. O’SiorainMariana P. Cervantes-SilvaLauren E. FaganShannon L. CoxEva Palsson-McDermottDavid K. FinlayEmma E. VincentEmma E. VincentNicholas JonesAnnie M. CurtisFrontiers Media S.A.articlemacrophage inflammationmetabolismmolecular clockIL-1βpSTAT3Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	macrophage inflammation metabolism molecular clock IL-1β pSTAT3 Immunologic diseases. Allergy RC581-607
spellingShingle	macrophage inflammation metabolism molecular clock IL-1β pSTAT3 Immunologic diseases. Allergy RC581-607 George A. Timmons Richard G. Carroll James R. O’Siorain Mariana P. Cervantes-Silva Lauren E. Fagan Shannon L. Cox Eva Palsson-McDermott David K. Finlay Emma E. Vincent Emma E. Vincent Nicholas Jones Annie M. Curtis The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
description	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.
format	article
author	George A. Timmons Richard G. Carroll James R. O’Siorain Mariana P. Cervantes-Silva Lauren E. Fagan Shannon L. Cox Eva Palsson-McDermott David K. Finlay Emma E. Vincent Emma E. Vincent Nicholas Jones Annie M. Curtis
author_facet	George A. Timmons Richard G. Carroll James R. O’Siorain Mariana P. Cervantes-Silva Lauren E. Fagan Shannon L. Cox Eva Palsson-McDermott David K. Finlay Emma E. Vincent Emma E. Vincent Nicholas Jones Annie M. Curtis
author_sort	George A. Timmons
title	The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
title_short	The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
title_full	The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
title_fullStr	The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
title_full_unstemmed	The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
title_sort	circadian clock protein bmal1 acts as a metabolic sensor in macrophages to control the production of pro il-1β
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/8e053272114849dda92fb87d549b098f
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The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β

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