Abstract
We found that circadian changes in ATP level in peripheral blood (PB) activate the Nlrp3 inflammasome, which triggers diurnal release of hematopoietic stem/progenitor cells (HSPCs) from murine bone marrow (BM) into PB. Consistent with this finding, we observed circadian changes in expression of mRNA for Nlrp3 inflammasome-related genes, including Nlrp3, caspase 1, IL-1β, IL-18, gasdermin (GSDMD), HMGB1, and S100A9. Circadian release of HSPCs from BM into PB as well as expression of Nlrp3-associated genes was decreased in mice in which pannexin 1-mediated secretion of ATP was inhibited by the blocking peptide 10Panx and in animals exposed to the specific small-molecule inhibitor of the Nlrp3 inflammasome MCC950. In addition to HSPCs, a similar decrease in diurnal cell counts was observed for mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). These results shed more light on the complexity of circadian regulation of HSPC release into PB, which is coordinated in a purinergic signaling-, innate immunity-dependent manner. Moreover, in addition to circadian changes in expression of the Nlrp3 inflammasome we also observed diurnal changes in expression of other inflammasomes, including Aim2, Nrp1a, and Nlrp1b.
Highlights
Circadian rhythms are internal processes that regulate the sleep– wake cycle and repeat every 24 h
In control animals we found a circadian pattern in the numbers of cells circulating in peripheral blood (PB), with the peak occurring in the late-morning hours (ZT5), which correlated with the highest level of circulating adenosine triphosphate (ATP) (Fig. 1) and peak activation of the Nlrp3 inflammasome (Fig. 2)
The salient observation of this study is that diurnal changes in the ATP level in PB activate the Nlrp3 inflammasome for release of stem cells from bone marrow (BM) into PB
Summary
Circadian rhythms are internal processes that regulate the sleep– wake cycle and repeat every 24 h. These processes are driven by a circadian clock and have been evolutionarily established in plants, fungi, bacteria, and animals, including mice and humans [1,2,3,4,5]. Stem Cell Rev and Rep (2020) 16:335–343. The number of circulating hematopoietic stem/progenitor cells (HSPCs) in peripheral blood (PB) follows a circadian rhythm pattern, with the peak occurring in the early morning hours and the nadir at night [3, 6, 9, 10]. In an elegant paper it was demonstrated that the timing of this peak can be explained by fluctuations in the tonus of the vegetative nervous system [4]
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