The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide

Abstract

Both sleep loss and pathogens can enhance brain inflammation, sleep, and sleep intensity as indicated by electroencephalogram delta (δ) power. The pro-inflammatory cytokine interleukin-1 beta (IL-1β) is increased in the cortex after sleep deprivation (SD) and in response to the Gram-negative bacterial cell-wall component lipopolysaccharide (LPS), although the exact mechanisms governing these effects are unknown. The nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome protein complex forms in response to changes in the local environment and, in turn, activates caspase-1 to convert IL-1β into its active form. SD enhances the cortical expression of the somnogenic cytokine IL-1β, although the underlying mechanism is, as yet, unidentified. Using NLRP3-gene knockout (KO) mice, we provide evidence that NLRP3 inflammasome activation is a crucial mechanism for the downstream pathway leading to increased IL-1β-enhanced sleep. NLRP3 KO mice exhibited reduced non-rapid eye movement (NREM) sleep during the light period. We also found that sleep amount and intensity (δ activity) were drastically attenuated in NLRP3 KO mice following SD (homeostatic sleep response), as well as after LPS administration, although they were enhanced by central administration of IL-1β. NLRP3, ASC, and IL1β mRNA, IL-1β protein, and caspase-1 activity were greater in the somatosensory cortex at the end of the wake-active period when sleep propensity was high and after SD in wild-type but not NLRP3 KO mice. Thus, our novel and converging findings suggest that the activation of the NLRP3 inflammasome can modulate sleep induced by both increased wakefulness and a bacterial component in the brain.

Protective effects of Genistein on the cognitive deficits induced by chronic sleep deprivation

“…Recently, growing lines of evidence had demonstrated that SD could trigger neuroinflammation and then resulted in neurobehavioral alterations including memory impairments (Xia et al, 2017;Zielinski et al, 2017). It was reported that pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6 are found to be increased upon SD in humans as well as experimental animals, and activation of NF-κB was shown in cortex and hippocampus regions of CSD rat (Manchanda, Singh, Kaur, & Kaur, 2018;Wadhwa et al, 2018).…”

Time Course of Blood and Brain Cytokine/Chemokine Levels Following Adolescent Alcohol Exposure and Withdrawal in Rats

“…EtOH can also effect microglial activation by altering the production and the activity of the inflammasome through the JAK/STAT signaling pathway. IL‐1β, IL‐18, HGMB1, and STAT have all been shown to be affected by EtOH and to alter neuronal excitability (Krueger et al, ; Kubota et al, ; Zielinski et al, ).…”

Sleep Fragmentation Induces Activation of NOD-Like Receptor Protein-3 Inflammasome in Rat Hippocampus

“…Levels of mature IL-1β, of NLRP-3 on spontaneous sleep and homeostatic sleep response following sleep deprivation (SD), NLRP-3 knockout (KO) mice showed no significant differences in IL-1β expression in the somatosensory cortex as well as caspase-1 activity following 6 h of SD compared with baseline, whereas wild-type mice showed elevated caspase-1 activity and NLRP-3, ASC, and IL-1β expression. 19 In the same study, NLRP-3 KO mice also showed reduced NREM sleep during the light period, and their homeostatic sleep responses following SD were attenuated. These findings suggest NLRP-3 activation as an important molecular mechanism for regulating SD-induced sleep response.…”