Harvard: 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
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