Article Impact Level: HIGH Data Quality: STRONG Summary of The FASEB Journal, 38(24), e70235. https://doi.org/10.1096/fj.202400508RR Dr. James R. O'Siorain et al.
Points
- Macrophage inflammasome activity, regulated by the circadian clock, varies throughout the day, with higher NLRP3 inflammasome activation and mitochondrial membrane potential (Δψm) observed at CT 12 compared to CT 0.
- Deleting the circadian gene Bmal1 in macrophages increased NLRP3 inflammasome activation, emphasizing its critical role in controlling inflammasome activity through mitochondrial function.
- Pharmacological disruption of mitochondrial membrane potential in synchronized macrophages reduced NLRP3 activation to baseline levels, linking mitochondrial health to circadian inflammasome regulation.
- The findings suggest that timing therapies targeting inflammasomes to specific times of day could improve efficacy, particularly for inflammatory conditions like arthritis, which often have morning symptom peaks.
- This research underscores the potential for time-targeted therapies to better manage inflammatory diseases by aligning treatment with the body’s circadian rhythms, minimizing unnecessary inflammation.
Summary
Macrophages are crucial immune cells that regulate inflammation, and recent research has revealed that their activity follows a daily rhythm, aligning with the body’s circadian clock. The NLRP3 inflammasome, responsible for cytokine release through pyroptosis, plays a significant role in this process. This study explored how the circadian rhythm influences NLRP3 inflammasome activation in macrophages, focusing on the role of mitochondria. The researchers found that peritoneal exudate cells (PECs) isolated at circadian time (CT) 12 exhibited heightened mitochondrial membrane potential (Δψm) and enhanced NLRP3 inflammasome activation compared to those at CT 0. Similarly, bone-marrow-derived macrophages (BMDMs) showed time-dependent differences in inflammasome activation when synchronized with the time of day. These findings suggest that the circadian clock regulates macrophage inflammasome activity through mitochondrial function.
The study further demonstrated that deletion of the myeloid-specific circadian gene Bmal1 resulted in increased NLRP3 inflammasome activation in PECs at CT 0 and unsynchronized BMDMs, compared to controls. This effect was mitigated when Δψm was pharmacologically disrupted in synchronized cells, reducing NLRP3 activation to baseline levels. These results underscore the importance of mitochondrial function in the circadian regulation of the NLRP3 inflammasome, highlighting that the activity of this immune response is modulated by both time-of-day and mitochondrial health, driven by Bmal1.
This research has profound implications for understanding the timing of immune responses and could pave the way for novel, time-targeted therapies for inflammatory diseases like arthritis. Given that symptoms of such conditions often worsen in the morning, when inflammasome activation is heightened, the findings suggest that treatments targeting inflammasomes might be more effective if administered at specific times of the day, optimizing patient outcomes and reducing unnecessary inflammation.
Link to the article: https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202400508RR
References O’Siorain, J. R., Cox, S. L., Payet, C., Nally, F. K., He, Y., Drewinksi, T. T., Kennedy, O. D., Dowling, J. K., Mellett, M., Early, J. O., & Curtis, A. M. (2024). Time‐of‐day control of mitochondria regulates NLRP3 inflammasome activation in macrophages. The FASEB Journal, 38(24), e70235. https://doi.org/10.1096/fj.202400508RR
