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

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, Nick Jones Orcid Logo, Annie M. Curtis

Frontiers in Immunology, Volume: 12

Swansea University Author: Nick Jones Orcid Logo

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DOI (Published version): 10.3389/fimmu.2021.700431

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 intracellula...

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Published in: Frontiers in Immunology
ISSN: 1664-3224
Published: Frontiers Media SA 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58614
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Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1&#x3B2;. 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-1&#x3B2; 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-1&#x3B2; 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. 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spelling 2022-10-27T11:17:55.1641095 v2 58614 2021-11-11 The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2021-11-11 BMS 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. Journal Article Frontiers in Immunology 12 Frontiers Media SA 1664-3224 macrophage inflammation, metabolism, molecular clock, IL-1b, pSTAT3 9 11 2021 2021-11-09 10.3389/fimmu.2021.700431 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University RCSI Strategic Academic Recruitment Program (StAR) award, a Science Foundation Ireland Career Development Award (17/CDA/4688) and an Irish Research Council Laureate Award (IRCLA/2017/110) 2022-10-27T11:17:55.1641095 2021-11-11T08:13:13.3178094 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine George A. Timmons 1 Richard G. Carroll 2 James R. O’Siorain 3 Mariana P. Cervantes-Silva 4 Lauren E. Fagan 5 Shannon L. Cox 6 Eva Palsson-McDermott 7 David K. Finlay 8 Emma E. Vincent 9 Nick Jones 0000-0003-4846-5117 10 Annie M. Curtis 11 58614__21716__cf34e0e508f8473f80290240cbf294b2.pdf 58614.pdf 2021-11-29T14:52:30.7850906 Output 7087828 application/pdf Version of Record true © 2021 Timmons, Carroll, O’Siorain, Cervantes-Silva, Fagan, Cox, Palsson-McDermott, Finlay, Vincent, Jones and Curtis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
spellingShingle The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
Nick Jones
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 The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
author_id_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
author Nick Jones
author2 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
Nick Jones
Annie M. Curtis
format Journal article
container_title Frontiers in Immunology
container_volume 12
publishDate 2021
institution Swansea University
issn 1664-3224
doi_str_mv 10.3389/fimmu.2021.700431
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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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.
published_date 2021-11-09T04:15:16Z
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