Summary: New research reveals how the body’s circadian clock regulates macrophage activity, influencing immune system inflammation throughout the day. Activation of the NLRP3 inflammasome, a key component in the immune response, peaks during the morning when macrophages are most efficient. This daily rhythm is driven by mitochondrial activity, explaining why inflammatory conditions like arthritis often worsen in the morning.
The findings open doors to time-targeted therapies, potentially improving treatments for diseases driven by overactive inflammasomes. Understanding the immune system’s internal clock could lead to precise interventions for inflammatory disorders.
Key Facts:
- Daily Immune Rhythms: The body’s clock regulates macrophage inflammasome activation, peaking in the morning.
- Mitochondrial Role: Mitochondria drive the time-dependent changes in immune response.
- Therapeutic Potential: Timing treatments to immune activity cycles could improve inflammatory disease management.
Source: RCSI
New research from RCSI University of Medicine and Health Sciences has explained how the body’s internal clock influences the inflammatory process of the immune system.
The findings describe how immune cells, called macrophages, work differently at various times of the day and could pave the way for time-targeted treatments for inflammatory diseases such as arthritis.
The researchers explored the link between the immune system and the body’s circadian rhythms often referred to as the body clock. Macrophages, immune cells that detect and respond to harmful substances, are able to trigger inflammation as a defense mechanism by assembling large complexes known as inflammasomes.
Inflammasomes could be compared to ‘smoke detectors’ that will then alert the immune system of danger.
Activation of an inflammasome called NLRP3 was not found to be constant throughout the day but was regulated by the body’s 24-hour circadian clock. This daily rhythm determines when macrophages are most efficient at detecting threats and when their energy levels peak to mount a response.
The research also highlights a key role for mitochondria, the cell’s energy producers, in driving these daily changes in immune activity.
“When macrophages ‘think’ it’s morning, their inflammasome activation is quicker and more robust,” explained Professor Annie Curtis, Principal investigator for the study at RCSI School of Pharmacy and Biomolecular Sciences.
“This means the immune response is heightened during the early part of the day, a time when we are awake and more likely to encounter environmental challenges, such as injuries or infections.”
The study has significant implications for understanding and treating inflammatory diseases, such as arthritis, where overactive inflammasomes play a key role. Symptoms of such diseases often worsen in the morning, something this research may help explain.
“With these findings, there’s potential to refine treatments for inflammatory conditions,” said Dr James O’Siorain, lead author of the study.
“For instance, new therapies targeting inflammasomes could be more effective if administered at specific times of the day when macrophage activity peaks.”
Funding: The research was supported by funding from Taighde Éireann – Research Ireland.
About this circadian rhythm and inflammation research news
Author: Laura Anderson
Source: RCSI
Contact: Laura Anderson – RCSI
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Time of day control of mitochondria regulates NLRP3 inflammasome activation in macrophages” by Annie Curtis et al. FASEB Journal
Abstract
Time of day control of mitochondria regulates NLRP3 inflammasome activation in macrophages
Macrophages are innate immune cells that orchestrate the process of inflammation, which varies across time of day. This ensures appropriate biological timing of the immune response with the external environment.
The NLRP3 inflammasome mediates IL-1-family cytokine release via pyroptosis. Mitochondria play a multifaceted role regulating NLRP3 inflammasome activity.
Mitochondria exhibit distinct metabolic changes across time of day, which are influenced by clock genes. However, whether the macrophage clock regulates the NLRP3 inflammasome via mitochondrial control remains unclear.
We find heightened mitochondrial membrane potential (Δψm) and enhanced NLRP3 inflammasome activation from peritoneal exudate cells (PECs) isolated at circadian time (CT) 12 compared to CT 0.
In vitro time-of-day synchronization of bone-marrow derived macrophages (BMDMs) induced time-dependent differences in NLRP3 inflammasome activation.
Myeloid-specific Bmal1-deletion enhanced NLRP3 inflammasome activity in PECs at CT0 and in unsynchronized BMDMs compared to controls.
Pharmacologically disrupting Δψm in synchronized cells reduced NLRP3 inflammasome activation to comparable levels, and the same occurred with Bmal1-deletion.
These results further demonstrate circadian clock timing of the NLRP3 inflammasome, which is dependent on mitochondrial function and driven through the circadian gene Bmal1.