Circadian Rhythms in NLRP3 Inflammasome Regulation: Possible Implications for the Nighttime Risk of Gout Flares

Abstract

Gout flares more frequently start late at night or in the early morning compared to during the day. The reasons for this are unknown. Activation of the NLRP3 inflammasome in monocytes/macrophages is central to initiation of gout flares. Here, we review the mechanisms by which circadian clocks control the NLRP3 inflammasome and the implications of this for the nighttime pattern of gout flares. Several hormones involved in inflammation regulation, e.g., glucocorticoids, melatonin and melanocortins, are under circadian control, with both circulating hormone levels as well as the expression of their receptors on target tissues showing time-of day differences. In addition, the NLRP3 inflammasome is also under the control of the macrophage circadian clock, leading to time-of-day differences in expression of NLRP3 inflammasome components and susceptibility to inflammasome-activating stimuli. MSU crystal exposure leads to altered expression of circadian clock components in macrophages, leading to time-of-day-specific loss of repression of NLRP3 inflammasome activity. Taken together, there is clear evidence that circadian clocks regulate the NLRP3 inflammasome and that this regulation may be compromised by MSU crystal exposure in gout. Circadian control of the inflammasome may be one of the factors contributing to nighttime susceptibility to gout flares.