A recent study has shown that circadian rhythms play a critical role in regulating the activity of the NLRP3 inflammasome through mitochondrial control. Life on Earth has evolved to anticipate environmental changes driven by the alternation of light and dark and the circadian molecular clock regulates these rhythms, not only at the systemic level but also at the cellular scale, influencing gene expression and protein synthesis through feedback loops. One key circadian gene, Bmal1, plays a crucial role in maintaining these rhythms and regulating various cellular functions.
Macrophages are integral to the immune response, particularly in inflammatory conditions, producing inflammatory cytokines like interleukin-1β (IL-1β) that are central to diseases such as asthma, rheumatoid arthritis, and psoriasis. Disruption of circadian rhythms, commonly caused by factors such as shift work, jet lag, and exposure to artificial light, has been linked to an increased risk of chronic inflammatory diseases.
The NLRP3 inflammasome, which processes and releases IL-1β, is central to macrophage-mediated inflammation. It is activated through a two-step process involving “priming” and “activation.” Priming leads to increased expression of inflammasome components such as NLRP3 and pro-IL-1β, while activation involves the assembly of inflammasome complexes and caspase-1-mediated processing of IL-1β. Caspase-1 cleavage of gasdermin D (GSDMD) triggers pyroptosis, leading to the release of IL-1β and other inflammatory cytokines.
Mitochondria play a pivotal role in regulating the NLRP3 inflammasome. Mitochondrial reactive oxygen species (ROS) enhance inflammasome activity, whereas mitochondrial-derived metabolites such as fumarate and itaconate have been shown to inhibit NLRP3 inflammasome activation. Mitochondrial membrane potential (Δψm) is essential for inflammasome activation, with its disruption leading to impaired NLRP3 inflammasome activity.
The study highlights the role of circadian rhythms in regulating NLRP3 inflammasome activity through mitochondrial control. It demonstrates that Δψm varies between peritoneal macrophages harvested at different circadian time points (CT0 and CT12), with higher Δψm correlating with increased NLRP3 inflammasome activity at CT12. Additionally, pharmacological inhibition of Δψm with FCCP significantly reduces inflammasome activation and IL-1β release, indicating a critical role of mitochondrial dynamics in time-of-day control of inflammation.
Notably, deletion of the circadian gene Bmal1 enhances NLRP3 inflammasome activity and disrupts Δψm, further supporting the role of circadian genes in regulating inflammasome function. These findings provide new insights into how circadian rhythms, through mitochondrial regulation, contribute to inflammatory responses and may underlie diseases characterized by chronic inflammation.
Katie Wright, EMJ
Reference
O’Siorain JR et al. Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages. FASEB J. 2024;38(24):e70235.
