Sleep deprivation induced elevated expression of High-mobility group box 1 () in cortical microglia and cerebrospinal fluids.
Neuroinflammation may be triggered by sleep deficit and is linked to various neurological disorders.
Sleep deprivation resulted in increased expression of the acetyltransferase p300 and decreased expression of the deacetylase SIRT1 in microglial cells.
The elevated levels of p300 led to increased acetylation, nuclear export, and secretion of HMGB1 following sleep deprivation.
Circadian clock protein interacts with p300 to inhibit its expression, a function that is compromised by sleep deprivation.
A mutant form of PER2 that cannot bind to p300 lost the ability to regulate p300 expression, highlighting PER2's role in controlling neuroinflammation.
Simplified
Lack of sleep is a common problem in current society, which can induce various brain dysfunctions. Neuroinflammation is a typical reaction caused by sleep deficit and is considered as a common basis for various neurological disorders and cognitive impairments, but the related mechanisms have not been fully clarified. The circadian clock protein plays a critical role in maintaining physiological homeostasis, including sleep/wake cycles. Circadian disorders induced by sleep deficit might contribute to the development of neuroinflammation. In the current study, we observed that sleep deprivation (SD) induced elevated expression of High-mobility group box 1 (), one of the most important mediators of neuroinflammation, in the cortical microglia and cerebrospinal fluids. Moreover, acetylation-dependent nuclear export of HMGB1 was involved in up-regulation and secretion of HMGB1 after sleep deprivation. Further studies indicated that sleep deprivation induced an increase in the expression of acetyltransferase p300 and a decrease in the expression of deacetylase SIRT1, which synergistically enhanced the acetylation level of HMGB1 in the cortical microglial cells, thereby triggered the nuclear export and secretion of HMGB1. Most importantly, circadian clock protein constitutively interacted with p300 and inhibited its expression in the microglial cells, which can be interrupted by PER2 downregulation upon sleep deprivation, leading to the increased expression of p300 and acetylation and secretion of HMGB1. The truncated PER2 mutant without p300 binding ability lost its ability to regulate p300 expression, indicating that PER2 functioned as a co-suppressor of p300 in regulating acetylation and expression of HMGB1. Taken together, data in this study reveal a new mechanism by which PER2 is involved in controlling HMGB1 dependent neuroinflammation induced by sleep deprivation. Maintaining PER2 levels or blocking HMGB1 acetylation in the cortex might be prospective for preventing sleep deprivation-induced neuroinflammation and the related adverse reactions in the brain.
Key numbers
1.8×
Level Increase
upregulation in microglial cells after sleep deprivation.
5×
p300 Expression Increase
p300 expression upregulated in BV2 cells after knockdown.
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Declarations. Competing interests: The authors declare no competing interests. Ethics approval: This study was performed in line with the international guidelines for the care and use of laboratory animals. Approval was granted by the by the Animal Ethics Committee of Beijing Institute of Basic Medical Sciences (No. IACUC-DWZX-2023-546).
