Morning Macrophage Activity Optimizes Inflammation Control

Inflammasomes are more active in the morning than the rest of the day. Macrophage activity, which regulates inflammation, is influenced by the biologic clock in the body. A team led by Annie Curtis, PhD, associate professor at the School of Pharmacy and Biomolecular Sciences at the Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland, found that these key immune cells are particularly active in the early morning and play a central role in initiating and regulating inflammatory processes.

Their findings, published in The FASEB Journal, offer insights into why symptoms of inflammatory diseases, such as arthritis, often worsen in the morning. They hope that therapies that follow a specific schedule will facilitate the treatment of these diseases in the future.

The study led by James O’Siorain, research assistant from Curtis’ group, and colleagues used human macrophages obtained from the peritoneum and bone marrow. These phagocytes, which belong to the leukocyte family and are part of the innate immune system, form inflammasome-protein complexes that react to certain stimuli such as infections, injuries, or metabolic imbalances by releasing interleukins (ILs), thus triggering an inflammatory reaction.

The authors reported that NOD-like receptor protein 3 (NLRP3) inflammasomes are particularly active in the early morning when macrophages are the most efficient.

“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,” Curtis explained in a press release from the RCSI.

Mitochondria and Circadian Rhythms

NLRP3 inflammasomes mediate the release of cytokines from the IL-1 family via pyroptosis, an inflammatory form of programmed cell death. Time-dependent changes in the immune system are apparently controlled by mitochondria. For example, the team observed a higher mitochondrial membrane potential in peritoneal macrophages in the morning than later in the day.

When the increased electrical voltage across the membrane was inhibited, NLRP3 inflammasome activity returned to normal, as observed at other times of the day. Consequently, macrophages reduce the release of IL-1 through pyroptosis.

However, the exact role of mitochondria in circadian immune responses remains unclear, the authors acknowledged.

Internal Clock Gene Influences Macrophages

Researchers have found that in the macrophages of the bone marrow, the gene Bmal1, which is part of the human internal clock and plays a key role in the development of circadian rhythms, also influences the activity of NLRP3 inflammasomes. When Bmal1 was deleted, inflammasomes showed heightened activity throughout the day, without a distinct peak in the morning.

“In summary, our study identifies a new model of time-of-day regulation of NLRP3 inflammasome and pyroptosis, which is mediated by mitochondrial membrane potential,” the authors concluded.

Timing Therapies

“With these findings, there’s potential to refine treatments for inflammatory conditions,” O’Siorain said in the press release. “For instance, new therapies targeting inflammasomes could be more effective if administered at specific times of the day when macrophage activity peaks.”

According to the researchers, overactive inflammasomes play a key role in arthritis and other inflammatory diseases.

This story was translated fromMedscape’s German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.