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George Timmons - Final Hardbound Copy of PhD Thesis for Final Printing - 12.10.2020.pdf (10.74 MB)

Regulation of Macrophage Glucose Metabolism by the Core Clock Protein BMAL1 and its Impact Upon the Inflammatory Response

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posted on 2022-02-16, 16:32 authored by George Timmons
The daily light-dark cycles have led to the generation of 24-hour circadian rhythms in most organisms on Earth. The molecular clock integrates external light signals and generates rhythmicity in many aspects of cellular processes, physiology and behaviour, allowing the organism adapt to its environment and improve survival. Disruption to circadian rhythms worsens chronic inflammatory pathologies such as cardiovascular disease, rheumatoid arthritis, and sepsis. At the molecular level, Bmal1 is the dominant clock gene, and its deletion ablates all rhythms. Macrophages mediate the inflammatory response and deletion of myeloid Bmal1 in mice leads to a dysfunctional response and increased severity of chronic inflammatory disease. However, the mechanisms underlying these effects are unclear. Our lab previously demonstrated that Bmal1-/- macrophages have a dysfunctional antioxidant response with increased levels of reactive oxygen species (ROS) and enhanced production of the pro-inflammatory cytokine IL-1β. However, it is now understood that macrophage cellular metabolism, also drives ROS and IL-1β production. Therefore, I sought to investigate whether BMAL1 is controlling metabolism in macrophages to impact on the inflammatory response.

I demonstrate that Bmal1-/- macrophages have increased metabolic output as a result of dysregulation at distinct metabolic nodes. These macrophages display increased glucose uptake, increased glycolytic metabolism, increased metabolic flux through the Krebs cycle, and increased levels of oxidative phosphorylation. Additionally, I demonstrate that these metabolic alterations are driving increased production of ROS and IL-1β. Specifically, increased levels of pyruvate kinase M2 and phosphorylated STAT3 and increased activity of succinate dehydrogenase are leading to enhanced IL-1β. Therefore, we propose 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 have unravelled new mechanisms by which the core molecular clock gene Bmal1 is controlling metabolism to dampen the inflammatory response. This may allow us to manipulate these pathways for therapeutic intervention in a range of chronic inflammatory diseases that are sensitive to the molecular clock.

History

First Supervisor

Dr Annie Curtis

Second Supervisor

Dr David Finlay

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2020

Published Citation

Timmons G,. Regulation of Macrophage Glucose Metabolism by the Core Clock Protein BMAL1 and its Impact Upon the Inflammatory Response [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020

Degree Name

  • Doctor of Philosophy (PhD)

Date of award

2020-11-30

Programme

  • Doctor of Philosophy (PhD)

Research Area

  • Immunity, Infection and Inflammation

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