We already know that sleep plays a protective role in resolving
infections. 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.
‘Sleep may be regulated in part by several brain-based immune proteins collectively called inflammasome NLRP3.’
A report on the team's findings was published 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
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.