Researchers have long studied how the body’s circadian rhythm influences immune function, with disruptions often linked to increased inflammation. A team from the Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences previously examined how immune cells called macrophages operate without a functional body clock. Now, their latest findings reveal how macrophages behave differently depending on the time of day, highlighting a potential for time-specific treatments for inflammatory diseases. Their findings also uncover a critical role for mitochondria in driving these daily immune fluctuations.
The findings are published in The FASEB Journal.
Macrophages release interleukin-1 (IL-1) cytokines in response to inflammatory stimuli, and the NLRP3 inflammasome mediates IL-1-family cytokine release via pyroptosis. Mitochondria play a multifaceted role regulating NLRP3 inflammasome activity. However, whether the macrophage clock regulates the NLRP3 inflammasome via mitochondrial control remains unclear.
The researchers observed activation of NLRP3 was not found to be constant throughout the day but was regulated by the body’s 24-hour circadian clock.
“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,” the researchers wrote. “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.”
“When macrophages ‘think’ it’s morning, their inflammasome activation is quicker and more robust,” explained Annie Curtis, PhD, a professor and 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.
The researchers believe their findings can improve treatments for inflammatory conditions, and pave the way for new therapies that could be more effective if administered at specific times of the day when macrophage activity peaks.
