Summary: Sleep may be regulated by inflammasome NLRP3, researchers report.
Sleep — one of the most basic, yet most mystifying processes of the human body — has confounded physicians, scientists and evolutionary biologists for centuries.
Now a study conducted in mice and led by investigators at Harvard Medical School and VA Boston Healthcare System reveals that sleep may be regulated in part by several brain-based immune proteins collectively called inflammasome NLRP3.
The researchers say the inflammasome — which works by unleashing a cascade of immune molecules in response to inflammation and infection — emerges as a central promoter of sleep following such events.
A report on the team’s findings was published Jan. 19 in Brain, Behavior and Immunity.
Scientists have known for a while that certain immune molecules enhance sleep and are activated by infection, but this is the first study suggesting a common underlying mechanism that regulates sleep and plays a critical role in recuperative sleep responses.
Results of the study show that the inflammasome recruits a sleep-inducing molecule to trigger somnolence following sleep deprivation and exposure to a bacterial toxin. Animals lacking genes for this protective immune complex showed profound sleep aberrations.”Our research points, for the first time, to the inflammasome acting as a universal sensing mechanism that regulates sleep through the release of immune molecules,” said study senior investigator Mark R. Zielinski, instructor in psychiatry at HMS.
Although warranting further study, the observations suggest that the inflammasome, the constellation of sleep-regulating proteins, may play an evolutionary role as a guardian of brain health and vitality that wards off the effects of sleep deprivation and infection.
“We already know that sleep plays a protective role in resolving infections so our observation of inflammasome activation following infection suggests this immune mechanism may have a brain-protective role,” Zielinski said.
If replicated in other studies, the researchers say the results may become the basis of therapies for people with chronic sleep disorders and sleep disturbances secondary to other diseases.
In a series of experiments, the scientists demonstrated that following sleep deprivation or exposure to bacteria, the inflammasome activates an inflammatory molecule called interleukin-1 beta, known to induce sleep and promote sleep intensity. The brain cells of mice lacking the gene coding for inflammasome NLRP3 showed a marked absence of this sleep-inducing molecule.
Going a step further, the investigators compared the behavior, sleep patterns and electrical activity in the brains of mice lacking the inflammasome gene to those in a group of mice with intact inflammasome genes.
Mice lacking the inflammasome gene had abnormal sleep responses following sleep deprivation. On average, such mice slept less and experienced more sleep interruptions than mice with their genes intact.
Electrical tracings of sleep activity were also altered in mice lacking the inflammasome NLRP3 gene. These animals lacked the normally seen spikes in delta waves–telltale EEG tracings that indicate sleep intensity, the researchers observed. Additionally, mice lacking the inflammasome NLRP3 gene did not show the normal sleepiness usually seen after exposure to a common sugar-and-fat molecule, a lipopolysaccharide found in the cell walls of some bacteria and known to activate the immune systems of mammals. These animals slept less and less soundly, compared with mice that had intact inflammasome genes. The latter group slept more and harder following bacterial exposure–the expected physiological response following infection, the researchers said.
In a final, proof-of-concept experiment, researchers gave sleep-inducing interleukin-1 beta to mice lacking inflammasome genes. Treatment with this molecule led to normalized sleep patterns. This finding, the researchers say, supports the notion that the inflammasome, which induces the secretion of sleep-promoting interleukin-1 beta, is indeed a critical regulator of sleep.
Co-investigators included Dmitry Gerashchenko, Svetlana Karpova, Varun Konanki, Robert McCarley, Fayyaz Sutterwala, Robert Strecker and Radhika Basheer.
Funding: The work was supported by the Department of Veterans Affairs Medical Research Service Award 2I01BX001404, Department of Veterans Affairs Medical Research Service Award I01BX002774, and Department of Veterans Affairs Career Award IBX002823A, NIMH-MH016259 fellowship, NINDS-NS079866, NINDS-NS064193, NIMH-MH039683, NHLBI-HL060292 and HL095491, and NIAID-AI118719.
Source: Ekaterina Pesheva – Harvard
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide” by Mark R. Zielinski, Dmitry Gerashchenko, Svetlana A. Karpova, Varun Konanki, Robert W. McCarley, Fayyaz S. Sutterwala, Robert E. Strecker, and Radhika Basheer in Brain, Behavior and Immunity. Published online January 19 2017 doi:10.1016/j.bbi.2017.01.012
[cbtabs][cbtab title=”MLA”]Harvard “Universal Immune Mechanism as a Regulator of Sleep.” NeuroscienceNews. NeuroscienceNews, 2 February 2017.
<https://neurosciencenews.com/sleep-immune-mechanism-6049/>.[/cbtab][cbtab title=”APA”]Harvard (2017, February 2). Universal Immune Mechanism as a Regulator of Sleep. NeuroscienceNew. Retrieved February 2, 2017 from https://neurosciencenews.com/sleep-immune-mechanism-6049/[/cbtab][cbtab title=”Chicago”]Harvard “Universal Immune Mechanism as a Regulator of Sleep.” https://neurosciencenews.com/sleep-immune-mechanism-6049/ (accessed February 2, 2017).[/cbtab][/cbtabs]
The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide
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.
“The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide” by Mark R. Zielinski, Dmitry Gerashchenko, Svetlana A. Karpova, Varun Konanki, Robert W. McCarley, Fayyaz S. Sutterwala, Robert E. Strecker, and Radhika Basheer in Brain, Behavior and Immunity. Published online January 19 2017 doi:10.1016/j.bbi.2017.01.012