Summary: New research identifies a key mechanism by which disruption of the circadian clock promotes inflammation in immune cells, with implications for common chronic diseases.
Source: RCSI
Researchers at RCSI have uncovered how an irregular or disrupted circadian clock in immune cells can reprogram their metabolism and drive a stronger inflammatory response, a discovery with potential relevance to many widespread human diseases.
Published in Frontiers in Immunology, this study was led by the School of Pharmacy and Biomolecular Sciences at RCSI University of Medicine and Health Sciences. The work clarifies how the molecular clockwork in macrophages — key innate immune cells — influences their fuel use and inflammatory behaviour.
The circadian body clock generates roughly 24-hour rhythms that coordinate physiology with the light/dark cycle. These rhythms help regulate many processes, including how immune cells such as macrophages respond to threats. When circadian timing is disturbed — by irregular sleeping and eating patterns, shift work, or insufficient daylight — immune cell rhythms can break down and the cells can become more prone to producing inflammatory molecules. Chronic inflammation of this type underlies or contributes to major conditions like heart disease, obesity, arthritis, diabetes and certain cancers, and it can also impair the body’s ability to fight infections.
In laboratory experiments, the team compared macrophages that retain a functioning cellular clock with macrophages lacking a key clock protein. They focused on how these cells use metabolic fuels, particularly glucose, and whether altered metabolism explains the increased inflammatory output seen when the clock is disrupted.
The researchers observed that macrophages deficient in the circadian clock protein took up substantially more glucose and processed it more rapidly through glycolysis than their clock-intact counterparts. Inside mitochondria, the downstream pathways that normally further break down glucose and produce cellular energy were also altered. These metabolic shifts promoted the generation of reactive oxygen species (ROS), which further amplify inflammatory signalling.
At the molecular level, the study identifies the transcription factor BMAL1 — a central circadian clock protein — as a critical metabolic sensor in macrophages. BMAL1 regulates glucose uptake and controls how glucose flows through glycolysis and the tricarboxylic acid (Krebs) cycle, including production of the metabolite succinate, which is linked to the production of the potent pro-inflammatory cytokine IL-1β. Loss of BMAL1 led to enhanced glycolysis and altered mitochondrial respiration, creating a metabolic profile that promotes a heightened pro-inflammatory state.
The research team also found that BMAL1 influences levels and cellular localization of the glycolytic enzyme PKM2. Changes in PKM2 activity were shown to activate the signalling protein STAT3, which in turn increases IL-1β mRNA expression, further connecting metabolic reprogramming to inflammatory gene production.
Dr George Timmons, lead author on the study, said: “Our results add to the growing body of work showing why disruption of our body clock leads to inflammatory and infectious disease, and one of the aspects is fuel usage at the level of key immune cells such as macrophages.”
Dr Annie Curtis, Senior Lecturer at RCSI School of Pharmacy and Biomolecular Sciences and senior author on the paper, added: “This study also shows that anything which negatively impacts our body clocks, such as insufficient sleep and reduced exposure to daylight, can impair the effective functioning of the immune system.”
The study was conducted at RCSI in collaboration with researchers from Swansea University, Trinity College Dublin and the University of Bristol.
About this inflammation and circadian rhythm research news
Author: Rosie Duffy
Source: RCSI
Contact: Rosie Duffy – RCSI
Image: The image is in the public domain
Original Research: Open access. “The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β” by George Timmons et al. Frontiers in Immunology
Abstract
The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β
BMAL1 is a core transcriptional component of the molecular circadian clock that shapes daily rhythms in many physiological processes, including the inflammatory behaviour of macrophages. Intracellular metabolic pathways are known to direct how macrophages respond during inflammation, but until now it has been unclear whether the cellular clock directly controls macrophage metabolism to shape that response.
This study demonstrates that BMAL1 regulates glucose uptake and its subsequent flux through glycolysis and the Krebs cycle, influencing levels of metabolites such as succinate that are important for driving IL-1β production. BMAL1 also modulates the amount and subcellular distribution of the glycolytic enzyme PKM2; altered PKM2 activity promotes activation of STAT3 and enhances Il-1β mRNA expression.
Overall, the findings identify BMAL1 as a key metabolic sensor in macrophages. Deficiency in this clock protein shifts macrophage metabolism toward increased glycolysis and altered mitochondrial respiration, which together promote a more pro-inflammatory phenotype. These insights improve our understanding of how disruption of molecular clocks can contribute to chronic inflammatory diseases and suggest potential avenues for time-based or metabolism-targeted interventions to limit macrophage-driven inflammation.