![mmune consequences of sleep deprivation. Sleep deprivation, as induced experimentally or in the context of habitual short sleep, has been found to be associated with alterations in the circulating numbers and/or activity of total leukocytes and specific cell subsets, elevation of systemic and tissue (e.g., brain) pro-inflammatory markers including cytokines (e.g., interleukins [IL], tumor necrosis factor [TNF]-α), chemokines and acute phase proteins (such as C reactive Protein [CRP]), altered antigen presentation (reduced dendritic cells, altered pattern of activating cytokines, etc.), lowered Th1 response, higher Th2 response, and reduced antibody production. Furthermore, altered monocytes responsiveness to immunological challenges such as lipopolysaccharide (LPS) may contribute to sleep deprivation-associated immune modulation. Hypothesized links between immune dysregulation by sleep deprivation and the risk for immune-related diseases, such as infectious, cardiovascular, metabolic, and neurodegenerative and neoplastic diseases, are shown. The illustrations were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. APC: antigenpresenting cells.](https://www.researchgate.net/publication/356352778/figure/fig1/AS:1094426315235328@1637942975225/mmune-consequences-of-sleep-deprivation-Sleep-deprivation-as-induced-experimentally-or_Q320.jpg)
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REVIEW ARTICLE
Role of sleep deprivation in immune-related
disease risk and outcomes
Sergio Garbarino 1✉, Paola Lanteri2, Nicola Luigi Bragazzi3,
Nicola Magnavita4,5 & Egeria Scoditti6
Modern societies are experiencing an increasing trend of reduced sleep duration, with noc-
turnal sleeping time below the recommended ranges for health. Epidemiological and
laboratory studies have demonstrated detrimental effects of sleep deprivation on health.
Sleep exerts an immune-supportive function, promoting host defense against infection and
inflammatory insults. Sleep deprivation has been associated with alterations of innate and
adaptive immune parameters, leading to a chronic inflammatory state and an increased risk
for infectious/inflammatory pathologies, including cardiometabolic, neoplastic, autoimmune
and neurodegenerative diseases. Here, we review recent advancements on the immune
responses to sleep deprivation as evidenced by experimental and epidemiological studies, the
pathophysiology, and the role for the sleep deprivation-induced immune changes in
increasing the risk for chronic diseases. Gaps in knowledge and methodological pitfalls still
remain. Further understanding of the causal relationship between sleep deprivation and
immune deregulation would help to identify individuals at risk for disease and to prevent
adverse health outcomes.
Sleep is an active physiological process necessary for life and normally occupying one-third
of our lives, playing a fundamental role for physical, mental, and emotional health1. Sleep
patterns and need are influenced by a complex interplay between chronological age,
maturation stage, genetic, behavioral, environmental, and social factors2–6. Adults should sleep a
minimum of 7 h per night to promote optimal health7,8.
Besides medical problems including obstructive sleep apnea and insomnia, factors associated
mostly with the modern 24/7 society, such as work and social demands, smartphone addiction,
and poor diet9–11, contribute to cause the current phenomenon of chronic sleep deprivation, i.e.,
sleeping less than the recommended amount or, better to say, the intrinsic sleep need12.
Sleep deprivation may be categorized as acute or chronic. Acute sleep deprivation refers to no
sleep or reduction in the usual total sleep time, usually lasting 1–2 days, with waking time
extending beyond the typical 16–18 h. Chronic sleep deprivation is defined by the Third Edition
of the International Classification of Sleep Disorders as a disorder characterized by excessive
daytime sleepiness caused by routine sleeping less than the amount required for optimal func-
tioning and health maintenance, almost every day for at least 3 months13.
Population studies reported a stably increasing prevalence of adults sleeping less than 6 h per
night over a long period12,14,15, also affecting children and adolescents16,17. Sleep duration
https://doi.org/10.1038/s42003-021-02825-4 OPEN
1Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal/Child Sciences, University of Genoa, 16132 Genoa, Italy.
2Neurophysiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 3Laboratory for Industrial and Applied Mathematics (LIAM),
Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada. 4Postgraduate School of Occupational Medicine, Università
Cattolica del Sacro Cuore, 00168 Rome, Italy. 5Department of Woman/Child and Public Health, Fondazione Policlinico Universitario Agostino Gemelli
IRCCS, 00168 Rome, Italy. 6National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy.
✉email: sgarbarino.neuro@gmail.com
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1234567890():,;
decline is present not only in high-income and developed
countries18 but also in low-income or racial/ethnic minorities19,
thus representing a worldwide problem.
In addition to fatigue, excessive daytime sleepiness, and
impaired cognitive and safety-related performance, sleep depri-
vation is associated with an increased risk of adverse health
outcomes and all-cause mortality20–24. Indeed, epidemiological
and experimental data support the association of sleep depriva-
tion with the risk of cardiovascular (CV) (hypertension and
coronary artery disease) and metabolic (obesity, type 2 diabetes
(T2DM)) diseases24–27. In the United States, sleep deprivation has
been linked to 5 of the top 15 leading causes of death including
cardio- and cerebrovascular diseases, accidents, T2DM, and
hypertension28. Data also point to a role for sleep deprivation in
the risk of stroke, cancer, and neurodegenerative diseases
(NDDs)26,29,30. Sleep deprivation is also associated with psy-
chopathological and psychiatric disorders, including negative
mood and mood regulation, psychosis, anxiety, suicidal behavior,
and the risk for depression31–36.
Both too short or too long sleep durations have been found to
be associated with adverse health outcomes and all-cause mor-
tality with an U-shaped relationship37–39. Although the relation
of long sleep duration to adverse health outcomes may be con-
founded by poor health conditions occurring in older adults37,
the causal association of sleep deprivation with negative health
effects is substantiated by experimental evidence providing bio-
logical plausibility24,40,41.
Sleep profoundly affects endocrine, metabolic, and immune
pathways, whose dysfunctions play a determinant role in the
development and progression of chronic diseases42–44. Specifi-
cally, in many chronic diseases, a deregulated/exacerbated
immune response shifts from repair/regulation towards unre-
solved inflammatory responses45.
Regular sleep is crucial for maintaining immune function
integrity and favoring a homeostatic immune defense to micro-
bial or inflammatory insults46,47. Sleep deprivation may result in
deregulated immune responses with increased pro-inflammatory
signaling, thus contributing to increase the risk for the onset and/
or worsening of infection, as well as inflammation-related chronic
diseases.
Here we reviewed the evidence regarding the impact of sleep
deprivation on immune-related diseases by discussing the major
points as follows: (1) the immune–sleep relationship; (2) the
association of sleep deprivation with the development and/or
progression of immune-related chronic diseases; and (3) the
immune consequences of sleep deprivation and their implications
for diseases. Finally, possible measures to reverse sleep
deprivation-associated immune changes were discussed.
Basic immune mechanisms of sleep regulation
The discovery of muramyl peptide, a bacterial cell wall compo-
nent that is able to activate the immune system and induce the
release of sleep-regulatory cytokines, primary regulators of the
inflammatory system, provided the first molecular link between
the immune system and sleep48. Thereafter, other microbial-
derived factors such as the endotoxin lipopolysaccharide (LPS)49,
as well as mediators of inflammation, such as the cytokines
interleukin (IL)-1 and tumor necrosis factor (TNF)-α, pros-
taglandins (PGs), growth hormone-releasing hormone (GHRH),
and growth factors, were recognized as sleep-regulating factors50.
Along this line, most animal studies have consistently shown a
role in particular for IL-1, TNF-α, and PGD
2
in the physiologic,
homeostatic non-rapid eye movement (NREM) sleep regulation,
so that the inhibition of their biological action resulted in
decreased spontaneous NREM sleep, whereas their
administration enhanced NREM sleep amount and intensity, and
suppressed rapid eye movement (REM) sleep51–53. Moreover, the
circulating levels of IL-1, IL-6, TNF-α, and PGD
2
are highest
during sleep54. Their effects are dose- and time-of-day-dependent
so that, for instance, low doses of IL-1 enhance NREMS, whereas
high doses inhibit sleep55. Reciprocal effects may be involved in
sleep regulation: for instance, the effects of systemic bacterial
products such as LPS may also involve TNF-α49. Links exist
between IL-1βand GHRH/growth hormone (GH) in promoting
sleep so that IL-1 induced GH release via GHRH56, and hypo-
thalamic γ-aminobutyric acid (GABA)ergic neurons (promoting
sleep) are responsive to both GHRH and IL-1β57. Instead, anti-
inflammatory cytokines, including IL-4, IL-10, and IL-13, inhib-
ited NREM sleep in animal models58.
Through these substances, the immune system may signal to
the brain and interact with other factors involved in sleep reg-
ulation such as neurotransmitters (acetylcholine, dopamine,
serotonin, norepinephrine, and histamine), neuropeptides
(orexin), nucleosides (adenosine), the hormone melatonin, and
the hypothalamus-pituitary axis (HPA) axis. Signaling
mechanisms to the brain also involve vagal afferents: for
instance, vagotomy attenuates intraperitoneal TNF-α-enhanced
NREMS responses59.
Cytokines are produced by a vast array of immune cells,
including those resident in the central nervous system (CNS), and
non-immune cells, e.g., neurons, astrocytes and microglia, and
peripheral tissue cells60,61. Cytokines interact with the
brain through humoral, neural, and cellular pathways, and form a
brain cytokine network (Fig. 1) able to produce cytokines, their
receptors, and amplify cytokine signals50. Peripheral cytokines
reach the brain through different non-exclusive mechanisms,
including blood–brain barrier (BBB) disruption62, penetration of
peripheral immune cells, and via afferent nerve fibers, such as the
vagus nerve, a bundle of parasympathetic sensory fibers that
conveys information from peripheral organs to the CNS63.
In the CNS, cytokines mediate a multiplicity of immunological
and nonimmunologic biological functions64, such as synaptic
scaling, synapse formation and elimination, de novo neurogen-
esis, neuronal apoptosis, brain development, cortical neuron
migration65, circuit homeostasis and plasticity66, and cortical
neuron migration65, and complex behaviors, sleep, appetite,
aging, learning and memory65, and mental health status67,68.
A common experimental finding is that after damage to any
brain area, if the animal or human survives, sleep always ensues69.
Recent evidence indicates that sleep is a self-organizing emergent
neuronal/glial network property of any viable network regardless
of size or location, whether in vivo or in vitro53,70–73. Several
sleep-regulatory substances, e.g., TNF, IL-1, nitric oxide, PGs, and
adenosine are all produced within local cell circuits in response to
cell use74,75.
From this point of view, TNF-αand IL-1 are closely inter-
connected and play a similar role in the regulation of sleep76–81.
IL-1βand TNF-αself-amplify and increase each other’s mRNA
expression in the brain82. In rats, IL-183 and TNF-α84 mRNAs
show diurnal variations in different brain areas, with the highest
concentrations recorded during increased sleep propensity and
peaks occurring at time of sleep period onset in rats and mice85.
Sleep-like states in mixed cultures of neurons and glia are
dependent in part on the IL-1 receptor accessory protein
(AcP)69,86. In the brain, there is an AcP isoform, neuron-specific
(AcPb)87, whose mRNA levels increase with sleep loss88,89. AcPb
is anti-inflammatory, whereas AcP is pro-inflammatory87,88.
TNF signaling promotes sleep, whereas reverse TNF-αsignal-
ing (the soluble TNF receptor) promotes waking90. The
brain production of TNF-αis neuron activity-dependent91.
Afferent activity into the somatosensory cortex enhances TNF
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expression92, and in vitro optogenetic stimulation enhances
neuronal expression of TNF immunoreactivity93.
Peripheral immune activation following acute or chronic
infection or inflammatory diseases is marketed by altered cyto-
kine concentrations and profiles, and is transmitted to the CNS
initiating specific adaptive responses. Among these, a sleep
response is induced and has been hypothesized to favor recovery
from infection and inflammation, supposedly via the timely
functional investment of energy into the energy-consuming
immune processes54,94. Accordingly, acute mild immune activa-
tion enhances NREM sleep and suppresses REM sleep, whereas
severe immune response with an upsurge of cytokine levels causes
sleep disturbance with the suppression of both NREM and REM
sleep49,95–98. This sleep change correlates to the course of the host
immune response as observed in bacterial and Trypanosoma
infections97,99. Supportively, the increase in NREM sleep was a
favorable prognostic factor for rabbits during infectious
diseases96.
Immune regulators also mediate the complex interrelation
between sleep and the circadian systems74. Circadian rhythms in
behavior and physiology are generated by a molecular clockwork
located in the suprachiasmatic nucleus, i.e., the master circadian
pacemaker, and peripheral tissues, and involving the so-called
clock genes (Clock,Bmals,Npas2,Crys,Pers,Rors, and Rev-
erbs)100. Cytokines, including TNF-α, IL-1β101,102, and
LPS103–105, suppress the peripheral and hypothalamic expression
of core clock genes and clock-controlled genes, resulting in
reduced locomotor activity accompanied by prolonged rest
time101.
Sleep deprivation and immune-related disease outcomes
In the following section, the association between sleep deprivation
and risk or outcomes of immune-related disorders, as observed in
human studies (mostly observational) and animal experimenta-
tions, will be examined. In this context, considering the
sleep–immunity relationship, research has also begun to explore
whether and how immune deregulation and inflammation may
link sleep deprivation with adverse health outcomes.
Infection. A breakdown of host defense against microorganisms
has been found in sleep-deprived animals, as shown by the
increased mortality after septic insult in sleep-deprived mice
compared with control mice106, or by systemic invasion by
opportunistic microorganisms leading to increased morbidity and
lethal septicemia in sleep-deprived rats107. There is growing
evidence associating longer periods of sleep with a substantial
reduction in parasitism levels108 and reduced sleep quality with
increased risk of infection and poor infection outcome109,110.
Accordingly, patients with sleep disorders exhibited a 1.23-fold
greater risk of herpes zoster than did the comparison cohort111.
Furthermore, sleep-deprived humans, as those with habitual short
sleep (≤5 h) compared with 7–8 h sleep, are more vulnerable to
respiratory infections in cross-sectional and prospective
studies112,113, and after an experimental viral challenge109,114.
Similarly, compared with long sleep duration (around 7 h), short
sleep duration (around 6 h) is associated with an increased risk of
common illnesses, including cold, flu, gastroenteritis, and other
common infectious diseases, in adolescents115.
Compared with non-sleep-deprived mice, REM-sleep-deprived
mice failed to control Plasmodium yoelii infection and, conse-
quently, presented a lower survival rate110. This was correlated to
an impaired T-cell effector activity, characterized by a reduced
differentiation of T-helper cells (Th) into Th1 phenotype and
following production of pro-inflammatory cytokines, such as
interferon (IFN)-γand TNF-α, and compromised differentiation
into T-follicular helper cells (Tfh), essential to B-cell maturation,
which therefore resulted to be reduced110. Accordingly, both Maf,
a Tfh differentiation factor, and T-bet, a pro-Th1 transcription
factor, were reduced in the REM-sleep-deprived group110. The
combination of REM-sleep deprivation and P. yoelii infection
Fig. 1 Brain cytokines (CYT, orange circles) network and different suggested routes by which peripherally released inflammatory signals can bypass
the blood–brain barrier and circumventricular organs (CVOs), and activate the central nervous system: humoral, cellular, and neural pathways. CCL-2:
C-C motif chemokine ligand-2; CXCL-10: C-X-C motif chemokine ligand 10; IL-1: interleukin-1; mNTS: medial nucleus tractus solitarius; PGE
2
: prostaglandin
E2; TNF-α: tumor necrosis factor-α.
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resulted in an additive effect on glucocorticoid synthesis, and
chemical inhibition of this exacerbated glucocorticoid synthesis
reduced parasitemia, death rate, and restored CD4 T-cell, Tfh,
and plasma B-cell differentiation in infected sleep-deprived
mice110, suggesting a role of HPA axis hyperactivation in
impairing host immune response under sleep deprivation.
Seep deprivation may exert detrimental effects on sepsis-
induced multi-organ damage. Sleep deprivation (3 days) after LPS
administration increased the levels of pro-inflammatory cytokines
(IL-6 and TNF-α) in the plasma and organs (lung, liver, and
kidney), which could be abrogated by subdiaphragmatic vagot-
omy or splenectomy 14 days prior to LPS administration116. Gut
microbiota-vagus nerve axis and gut microbiota-spleen axis may
play essential roles in post-septic sleep deprivation-induced
aggravation of systemic inflammation and multi-organ
injuries116.
Considering the association between sleep deprivation and
immune response to infections, vaccination studies allow to assess
the impact of sleep and sleep loss on ongoing immune response
and the clinical outcome. Studies in which sleep deprivation (one
or few nights) was applied to healthy humans during (mostly
after) the immunological challenge of vaccination demonstrate
that sleep deprivation reduced both the memory and effector
phases of the immune response, as indexed by suppressed
antigen-specific antibody and Th cell response compared with
undisturbed sleep117.
Congruently, habitual (and hence chronic) short sleep duration
(<6 h) compared with longer sleep duration was associated with
reduced long-term clinical protection after vaccination against
hepatitis B118. Sleep deprivation did not exert any impairing effect
on mice already immunized119. From these studies, it seems that
sleep supports—and sleep deprivation impedes—the formation of
the immunological memory. Potential mechanisms involved in
the beneficial effect of normal sleep on the vaccination response
include: (i) the sleep-induced reduction in circulating immune
cells that most likely accumulate into lymphatic tissues,
increasing the probability to encounter antigens and trigger the
immune response; (ii) the sleep-associated profile of inflamma-
tory activation towards Th1 cytokines (increased IL-2, IFN-γ,
etc.), which may favor macrophage activation, antigen presenta-
tion, and T-cell and B-cell activation; (iii) the effect of sleep stage
on the formation of immunological memory through specific
immune-active hormones: indeed, during slow wave sleep-rich
early sleep, the profile of immune-active hormones, characterized
by minimum concentrations of cortisol, endowed with anti-
inflammatory activity, and high levels of GH, prolactin, and
aldosterone, which support Th1 cell-mediated immunity, may
facilitate the mounting of an effective adaptive immune response
to a microbial challenge54.
Cancer. Sleep deprivation has increasingly been recognized as a
risk factor for impaired anti-tumor response. Epidemiological
studies suggest, albeit not consistently120, a significant association
between short sleep duration and the risk for several cancers,
including breast, colorectal, and prostate cancer29,121–123.
Potential mechanisms underlying this association include a
shorter duration of nocturnal secretion of melatonin (putatively
due to increased light exposure at night)124, which exerts anti-
cancer properties through antimitotic, antioxidant, apoptotic,
anti-estrogenic, and anti-angiogenic mechanisms125. Melatonin
also plays immunomodulatory and anti-inflammatory effects with
relevance for its anti-cancer activity, being able to inhibit the pro-
inflammatory nuclear factor-κB (NF-κB)/NLRP3 inflammasome
pathways, and to support T/B-cell activation and macrophage
function126. However, besides melatonin, impaired anti-tumor
immune response has been invoked in the sleep deprivation-
associated risk for cancer development. A reduced cytotoxic
activity of natural killer (NK) cells, which are immune cells with
anti-tumor effect, has been reported in 72 h sleep-deprived mice
compared with control mice, accompanied by reduced numbers
of the cytotoxic cells such as CD8 T cells and NK cells in the
tumor microenvironment after chronic sleep deprivation (for
18 h/day during 21 days) in an animal model of experimental
pulmonary metastasis127,128. In this model, the reduced anti-
tumor immunity of sleep-deprived animals was also indexed by
the reduced number of antigen-presenting cells (dendritic cells)
in the lymph nodes, as well as by the decreased effector CD4
T-cell numbers and corresponding cytokine profile (decreased
IFN-γ), resulting in lowered Th1 response of Th cells, i.e., the
most effective immune response against tumors. Therefore, an
immunosuppressive environment develops with sleep depriva-
tion, which could translate into an early onset and increased
growth rate of cancer128 or increased mortality129.
An integrated meta-analysis of transcriptomic data showed
that circadian rhythm-related genes are downregulated and
upregulated in the cortex and hypothalamus samples of mice
with sleep deprivation, respectively, with downregulated genes
associated with the immune system and upregulated genes
associated with oxidative phosphorylation, cancer, and
T2DM130. Several circadian rhythm-related genes were common
to both T2DM and cancer, and seem to associate with malignant
transformation and patient outcomes130.
Hence, although these sleep deprivation-induced immune-
mediated mechanisms in cancer warrant further confirmation in
humans, the importance of the immune function in the anti-
tumor host defense is well recognized131, thus suggesting that the
impaired immune response after sleep deprivation may represent
a plausible mediator of the associated increased risk for cancer as
described in animal models and in humans.
Neurodegenerative diseases. NDDs are aging-related diseases
that selectively target different neuron populations in the CNS,
and include Alzheimer’s disease, multiple sclerosis, Parkinson’s
disease, Huntington’s disease, and amyotrophic lateral sclerosis.
One prevailing hypothesis is that altered sleep habits and speci-
fically sleep deprivation may be a consequence and frequently a
marker of the disease132–134. However, human and animal studies
have also suggested a causative or contributing role for sleep
deprivation in the development and/or worsening of neurode-
generative processes132–134.
Potential pathophysiological mechanisms involve, among
others, neuro-immune dysregulation. Indeed, a common feature
–and a potential therapeutic target- of NDDs is the chronic
activation of the immune system, where aspects of peripheral
immunity and systemic inflammation integrate with the brain’s
immune compartment, leading to neuroinflammation and
neuronal damage135. Neuroinflammation following sleep depri-
vation has been studied as a pathogenic mechanism potentially
mediating the association between sleep deprivation and
neurodegenerative processes. Low-grade neuroinflammation as
indexed by heightened levels of pro-inflammatory mediators (e.g.,
TNF-α, IL-1β, and COX-2) and activation of astrocytes and
microglia, main immune cells in the brain, was observed in the
hippocampus and piriform cortex regions of the brain of chronic
sleep-deprived rats along with neurobehavioral alterations
(anxiety, learning, and memory impairments)136. The sleep
deprivation pro-inflammatory milieu was accompanied by
oxidative stress in the brain137 and BBB disruption with
consequent increased permeability to blood components138. After
acute sleep deprivation, there was a significant increased
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recruitment of B cells in the mouse brain, which could be
important given evidence of B cells involvement in NDDs139.
Progressive and chronic aggregations of unique proteins in the
brain and spinal cord are hallmarks of NDDs140 and trigger
inflammatory responses, gradual loss of physiological functions of
the nerve cells, and cell death141. Impaired autophagy in humans,
a catabolic process of cytoplasmic components, contributes to the
aggregation and accumulation of β-amyloid (Aβ), cytoskeleton-
related protein τ, and synuclein in neuronal cells and tissues140.
Sleep plays an important role in the clearance of metabolic waste
products accumulated during wakefulness and neural activity.
Indeed, the Aβprotein is predominantly cleared from the brain
during sleep, possibly through the glymphatic pathway. Con-
gruently, acute and chronic experimental sleep deprivation in
animals142,143 and humans144 resulted in brain Aβaccumulation
and plaque formation, a typical pathological change in Alzhei-
mer’s disease process, the most common type of dementia.
Imaging studies have revealed that healthy humans with self-
reported short sleep were more prone to have cerebral Aβplaque
pathology145 and disruption of deep sleep (slow wave sleep)
increases Aβin human cerebrospinal fluid (CSF)146. Likewise,
patients with insomnia present higher CSF levels of Aβ147.
This pathological Aβaccumulation might reflect disrupted
balance of Aβproduction and clearance after sleep deprivation.
On the one hand, sleep deprivation results in reduced clearance as
suggested by clinical studies showing that Aβlevels in CSF are the
highest before sleep and the lowest after wakening, whereas Aβ
clearance from CSF was impaired by sleep deprivation148.
Impaired clearance might also derive from disrupted peripheral
Aβtransport, as suggested by the sleep deprivation-induced
downregulation of low-density lipoprotein receptor-related pro-
tein-1 (LRP-1), which promotes Aβefflux from the brain to the
peripheral circulation across the BBB, and elevations of receptor of
advanced glycation end products (RAGE), which promotes on the
contrary the influx of peripheral Aβinto the brain, thus
preventing Aβclearance149. On the other hand, apart from
impairing Aβand τinterstitial fluid clearance, sleep deprivation
may also have a role in increasing Aβand τexocytosis, thereby
increasing CSF Aβand τlevels150. In animals, sleep deprivation
also leads to upregulation of β-secretase 1 (BACE-1), the most
important enzyme regulating Aβgeneration in the brain142,143,149,
thus opening the hypothesis of increased Aβproduction by sleep
deprivation. Sleep deprivation-induced neuroinflammatory med-
iators correlate and could lead to disturbed Aβclearance and
stimulated amyloidogenic pathway143, being pro-inflammatory
cytokines able to suppress the expression of LRP-1 and to increase
RAGE151 and BACE-1 levels152. Likewise, oxidative stress induced
by sleep deprivation may also contribute to the neuroinflamma-
tory burden and the increased expression of BACE-1153.
Furthermore, patients with insomnia, compared with healthy
controls, showed decreased serum levels of neurotrophins,
including brain-derived neurotrophic factor (BDNF), proteins
especially relevant in neuroplasticity, memory and sleep, and this
reduction was significantly related to the insomnia severity154.
Sleep deprivation is associated with a rapid decline in
circulatory melatonin levels, which may be linked to rapid
consumption of melatonin as a first-line defense against the sleep
deprivation-associated rise in oxidative stress155. Melatonin is a
potent antioxidant, interacts with BDNF156, and promotes
neurogenesis and inhibits apoptosis157. The neuroprotective
potential of melatonin can target events leading to Alzheimer’s
disease development including Aβpathology, τhyperphosphor-
ylation, oxidative stress, glutamate excitotoxicity, and calcium
dyshomeostasis150,158. Accordingly, melatonin treatment could
restore the autophagy flux, thereby preventing tauopathy and
cognitive decline in Alzheimer’s disease mice159.
Patients with Alzheimer’s disease have an increased incidence
of sleep-disordered breathing160. In addition, sleep-disordered
breathing is associated with an increased risk of mild cognitive
impairment or dementia and with earlier onset of Alzheimer’s
disease161. Sleep-disordered breathing is also associated with
altered levels of Alzheimer’s disease biomarkers in CSF, including
decreased levels of Aβand elevated levels of phosphorylated τ162.
Sleep-disordered breathing possibly via hypoxia, inflammation,
and sleep disruption/deprivation could contribute to Alzheimer’s
disease processes, e.g., increase of Aβproduction and aggregation,
suppression of glymphatic clearance of Alzheimer’s disease
pathogenic proteins (τ,Aβ) and oxidative stress, inflammation,
and synaptic damage134,163.
To summarize, the sleep deprivation-associated risk for
Alzheimer’s disease could be linked to the induction of
inflammation in the brain and disorders of systemic innate and
adaptive immunity164. However, the relationship of sleep
deprivation to inflammation in Alzheimer’s disease is mostly
speculative and needs to be confirmed.
Similar to Aβin Alzheimer’s disease, abnormal levels of α-
synuclein are common to Parkinson’s disease, the second most
common NDDs165. Sleep disturbances are not only a common
comorbidity in Parkinson’s disease, but often precede the onset of
classic motor symptoms166. The main pathological features of
Parkinson’s disease are the reduction of dopaminergic neurons in
the extrapyramidal nigrostriatal body and the formation of Lewy
bodies formed by the aggregation of α-synuclein and its oligomers
surrounded by neurofilaments. Due to the degeneration of the
dopaminergic neurons, affected people show muscle stiffness,
resting tremors, and posture instability; other pathways involved
in sleep, cognition, mental abnormalities, and other non-motor
symptoms are also affected167. Epidemiological studies also
suggest that disturbed sleep may increase the risk of Parkinson’s
disease168,169. Such disease-modifying mechanisms may include
activation of inflammatory and immune pathways, abnormal
proteostasis, changes in glymphatic clearance, and altered
modulation of specific sleep neural circuits that may prime
further propagation of α-synucleinopathy in the brain169.
Melatonin could reduce neurotoxin-induced α-synuclein aggre-
gation in mice. Furthermore, melatonin pretreatment reduced
neurotoxin-induced loss of axon and dendritic length in
dopaminergic neurons through suppression of autophagy acti-
vated by CDK5 and α-synuclein aggregation, thereby reducing
dyskinesia symptoms in Parkinson’s disease animal models170.A
few reports have shown that melatonin exerts protective effects in
several experimental models of Parkinson’s disease171.
However, although animal experimentations suggest a link
between sleep deprivation and immune dysfunction in neurode-
generative processes, no human investigations have yet confirmed
the mediating role of immune dysregulation in the association
between sleep deprivation and risk or outcomes of NDDs.
Autoimmune diseases. Sleep disturbances are frequently reported
in autoimmune diseases, and immunotherapy in patients with
autoimmune pathologies results in sleep improvement172. However,
knowledge of the immunopathology of autoimmune diseases have
disclosed new concepts on the impact of sleep deprivation on
autoimmune disease process, showing that sleep deprivation can
promote a breakdown of immunologic self-tolerance. Human
cohort studies found that non-apnea sleep disorders, including
insomnia, were associated with a higher risk of developing auto-
immune diseases such as rheumatoid arthritis, ankylosing spon-
dylitis, systemic lupus erythematosus, and systemic sclerosis
(adjusted hazard ratio: 1.47, 95% confidence interval (CI)
1.41–1.53)173 Similarly, in relatives of systemic lupus erythematosus
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patients, and hence at increased risk for systemic lupus erythema-
tosus, self-reported short sleep duration (<7 h/night) was associated
with transitioning to systemic lupus erythematosus (adjusted odds
ratio: 2.0, 95% CI 1.1–4.2), independent of early preclinical features
that may influence sleep duration such as prednisone use, depres-
sion, chronic fatigue, and vitamin D deficiency174.Thisroleofsleep
deprivation as a risk factor for autoimmune diseases is corroborated
by animal studies. In mice genetically predisposed to develop sys-
temic lupus erythematosus175, chronic sleep deprivation, applied at
an age when animals were yet clinically healthy, caused an early
onset of the disease, as indexed by the increased number of anti-
nuclear antibodies, without affecting disease course or severity,
according to data on proteinuria, a surrogate marker of auto-
immune nephritis, and longevity. Several mechanisms have been
postulated to explain the link between sleep deprivation and auto-
immune disease risk. Sleep deprivation can accelerate disease
development through mechanisms including sleep deprivation-
induced increased production of several pro-inflammatory
cytokines44,54, as better discussed below. Indeed, cytokines are
synergistically involved in the pathogenesis of autoimmunity, such
as IL-6, whose abnormal production results in polyclonal B-cell
activation and the occurrence of autoimmune features176,andIL-17
and the related Th17-cell response177, which require IL-6 for
activation178 and can cause greater amounts of autoantibody pro-
duction and immune complex formation, or can intensify chronic
inflammation by promoting angiogenesis and recruiting of
inflammatory cells at inflammationsitesaswellascartilageand
bone erosion179. Furthermore, experimentally sleep-deprived heal-
thy humans showed impaired suppressive activity of CD4 reg-
ulatory T cells (Treg), which normally is highest during the night
and lowest in the morning180. The suppressive function of Treg
towards excessive immune response is an important homeostatic
mechanism, whose impairment is implicated in autoimmune dis-
ease pathogenesis181. Hence, sleep deprivation may not be merely
an early symptom or a consequence of an autoimmune disease, but
may contribute directly to the pathogenesis increasing the sus-
ceptibility to develop an autoimmune disease. More studies are
warranted in this field.
Metabolic and vascular diseases. Prospective epidemiological
evidence associate sleep deprivation (commonly <7 h/night, often
<5 h/night) with the incidence of fatal and non-fatal CV out-
comes, with a 48% higher risk of coronary heart disease25, a 15%
higher risk of stroke182, and a 12% increased risk of all-cause
mortality37, which is mainly due to CV causes, according to some
authors183. In a recent prospective cohort, a low-stable sleep
pattern (<5 h sleep/night) during the 4-year follow-up had the
highest risk of death and CV events184. Short sleep has also been
associated with increased subclinical atherosclerotic burden, the
dominant underlying cause of CV diseases185.
In addition, sleep deprivation increases the risk for obesity
(about 55% higher risk)39,186, insulin resistance, T2DM (28%
higher risk)38, and hypertension (21% higher risk)187, which are
powerful and preventable risk factors for CV diseases. Notably,
the risk for diabetes attributable to sleep deprivation is
comparable to that of other established traditional cardiometa-
bolic risk factors188, thus underscoring the clinical significance of
targeting sleep deprivation in the prevention of cardiometabolic
diseases. In contrast with normal nocturnal sleep and in
particular NREM sleep characterized by a marked decrease in
sympathetic activity, catecholamine plasma levels, and blood
pressure, experimental sleep deprivation (acute or chronic) is
accompanied by increased sympathetic outflow, with consequent
higher blood pressure and heart rate, thus providing a pathogenic
link between sleep deprivation and hypertension risk189–192.
Regarding the influence of sleep deprivation on metabolic
pathways, studies support a plausible causal link between sleep
deprivation and the risk of overweight and obesity, possibly
mediated by the effect of sleep deprivation on circulating levels of
hormones (leptin, ghrelin) controlling hunger, satiety and energy
balance, besides other factors intervening during sleep depriva-
tion, including physical inactivity and overfeeding193. Further-
more, human experimental evidence with chronic sleep
deprivation protocol demonstrate that sleep deprivation may
alter glucose metabolism194 and insulin sensitivity195, thus
increasing the risk for obesity and T2DM. The reduction in total
body insulin sensitivity observed after sleep deprivation (4.5 h per
night for 4 days) in healthy subjects was paralleled by impaired
peripheral insulin sensitivity, as demonstrated in subcutaneous fat
playing a pivotal role in energy metabolism195. Considering a
more chronic sleep deprivation, reduced insulin sensitivity was
reported in overweight adults after 14 days of experimental sleep
deprivation (5.5 h per night) compared with 8.5 h per night of
sleep196, and after habitual curtailment in sleep duration of 1.5 h
(<6 h of sleep per night) in healthy young adults with a family
history of T2DM197.
Although the mechanisms that underlie most associations
between short sleep duration and adverse cardiometabolic
outcomes are not fully understood, potential causative mechan-
isms involving immune-inflammatory activation have been
postulated. It is indeed well established that the subclinical
inflammatory status induced by sleep deprivation has pathogenic
implications for metabolic and CV risk factors (glucose
metabolism, diabetes, hypertension, atherogenic lipid profile,
endothelial dysfunction, and coronary calcification) and out-
comes (stroke and coronary heart disease)24. Accordingly, most
of the markers of systemic and cellular inflammation (leukocyte
counts and activation state, cytokines, acute-phase proteins, and
adipose tissue-derived adipokines) found to be altered after sleep
deprivation have been epidemiologically and pathogenically
associated with insulin resistance, T2DM, and vascular
complications198. In fact, inflammation is an early pathogenic
process during the development of obesity and insulin
resistance199. Many adipose tissue-released inflammatory factors
with pro-atherogenic and pro-thrombotic actions have also been
regarded as a molecular link between obesity and atherosclerotic
CV diseases200. Furthermore, chronic inflammatory processes are
firmly established as central to the development and clinical
complications of CV diseases, form the initiation, promotion and
progression of atherosclerotic lesions to plaque instability, and the
precipitation of thrombosis, the main underlying cause of
myocardial infarction or stroke. Most CV risk factors (adiposity,
insulin resistance, T2DM, hypertension, and dyslipidemia) act by
inducing or intensifying such underlying inflammatory processes
that ultimately promote endothelial dysfunction, altered vascular
reactivity, innate and adaptive immune system activation,
leukocyte infiltration into the vessel wall, and thus
atherogenesis201. Experimental sleep deprivation leads to
endothelial dysfunction, an early marker of atherosclerosis, as
indexed by impaired endothelial-dependent vasodilation or
increased levels of endothelial adhesion molecules191.
Among the inflammatory markers, besides being a biomarker
of future risk for CV diseases and a predictor of clinical response
to statin therapy202, C-reactiove protein (CRP) has been shown to
be involved in the immunologic process that triggers vascular
remodeling and atherosclerotic plaque deposition202. CRP levels
lack diurnal rhythm and its liver production is stimulated by
cytokines including IL-6 and IL-17, which are upregulated by
sleep deprivation203. As such, although limited evidence have
found an elevation of circulating CRP following sleep
deprivation204, CRP is a prototypical inflammatory factor with
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the potential to mark and—to some extent mediate—CV risk
following sleep deprivation. Congruently, elevated and sustained
plasma levels of CRP have been observed in healthy humans after
prolonged sleep deprivation (5 or 10 nights), in concomitance
with increased heart rate190,203, lymphocyte pro-inflammatory
activation, and production of cytokines (e.g., IL-1, IL-6, and IL-
17)203. Similarly, the increase in blood pressure and heart rate
observed after acute total sleep deprivation (40 h) was accom-
panied and even preceded by impaired vasodilation and by
increased levels of IL-6 and markers of endothelial dysfunction
and activation, such as cellular adhesion molecules (E-selectin,
ICAM-1, etc.)191. The sleep deprivation pro-atherogenic effect in
animal model of sleep fragmentation is mediated, at least in part,
by reduced hypothalamic release of hypocretin (i.e., orexin), a
wake-inducing neuropeptide, which limits the production of
leukocytes (monocytes and neutrophils) and atherosclerosis
development, and has been inversely associated with the risk of
myocardial infarction, heart failure, and obesity205. The activation
of the sympathetic nervous system (SNS) may be another
mechanism for the inflammatory link between sleep loss and
atherosclerotic CV disease, because such activation increases the
bone marrow release of progenitor cells, the production of innate
immune cells (monocytes), and the levels of inflammatory
cytokines, and triggers endothelial dysfunction, thereby leading
to systemic and vascular inflammation and atherosclerosis206,207.
Playing a key role in instigating inflammatory responses and
promoting atherosclerosis208, the sleep deprivation-associated
oxidative stress may also contribute to CV risk. It has also been
hypothesized a role for melatonin suppression following sleep
deprivation in the vascular impairment associated with sleep
deprivation, given that melatonin inhibits oxidative stress and
cytokine production by immune and vascular cells, and represses
atherosclerotic lesion formation in vivo209.
Therefore, a significant and consistent association exists
between sleep deprivation and cardiometabolic risk and clinical
outcomes, with several plausible immune-mediated causative
mechanisms explaining this association.
Immune mechanisms linking sleep deprivation and diseases
As shown above, sleep deprivation has been found to alter
inflammatory immune processes via multiple pathways, which
could lead to increased susceptibility to chronic inflammatory
diseases (Fig. 2). Most of the current knowledge on immune
effects of sleep deprivation come from studies using controlled
experimental sleep deprivation protocols, among which chronic
partial sleep deprivation, lasting 2–15 days, is that mostly
resembling the human condition of chronic insufficient sleep.
Some studies have observed that sleep deprivation, compared
with regular nocturnal sleep, leads to increased circulating
numbers of total leukocytes and specific cell subsets mainly
neutrophils, monocytes, B cells, CD4 T cells, and decreased cir-
culating numbers and cytotoxic activity of NK cells203,210–213.
Other studies, however, found contrasting results, including a
decrease in CD4 T cells after sleep deprivation213,214, probably
due to differences in sleep deprivation protocol, sampling meth-
odologies, and other factors. Sleep deprivation has also shown to
alter circadian rhythm of circulating leukocytes215, with higher
levels during the night and at awakening and a flattened
rhythm210,212. Additional findings are suggestive of immune
deregulation by sleep deprivation, including a decreased neu-
trophils phagocytic activity213, altered lymphocytes adhesion
molecule expression216, and reduced stimulated production of IL-
2 and IL-12, which are important for adaptive immunity211,217.
Experimental sleep deprivation has been reported to affect
systemic markers of inflammation, with studies showing
increased circulating pro-inflammatory molecules (IL-1, IL-6,
CRP, TNF-α, and MCP-1); this associated in some studies with a
subsequent homeostatic increase in endogenous inhibitors,
including IL-1 receptor antagonist and TNF receptors203,218–220.
In agreement with experimental sleep deprivation, population
studies found a direct independent association between habitual
short sleep duration (generally < 5 or 6 h) and elevated circulating
pro-inflammatory markers, e.g., acute phase proteins (CRP and
IL-6), cytokines (TNF-α, IFN-γ, IL-1, etc.), adhesion molecules,
and leukocyte counts183,221–225. Furthermore, a reduced NK cell
activity226 and a decline in naive T cells227, compatible with
reduced immune competence, was reported in association with
habitual short sleep. Shortening of leukocyte telomere length, a
cellular senescence marker linked with inflammation, was also
associated with shorter sleep duration228,229.
The reported elevation of systemic inflammation is clinically
relevant, because it is suggested to specifically mediate the
increased risk of mortality associated with short sleep23,230,231
and, as observed, the risk for chronic disease development.
Regarding cellular markers of inflammation, some studies
found that the ex-vivo LPS-stimulated production of TNF-
α232,233, IL-1β, and IL-6203,232–234 by human monocytes
increased during sleep deprivation but decreased during regular
nocturnal sleep54,203,232–234. However, other studies reported a
decrease of TNF-αproduction by activated monocytes after sleep
deprivation compared with regular nocturnal sleep203,235. These
contrasting results need further investigations and may depend
on differences in the cytokine sensitivity to different sleep
deprivation protocols or sampling methods and time. For
instance, it seems that partial acute sleep deprivation increased
stimulated monocytic TNF-αproduction232,233, whereas more
sustained sleep deprivation decreased it203,235.
Undisturbed sleep is predominantly characterized by a Th1
polarization of Th cells (expressing IFN-γ, IL-2, and TNF-α), and
experimental sleep deprivation in humans leads to a shift from a
Th1 pattern towards a Th2 pattern (expressing IL-4, IL-5, IL-10,
and IL-13)217,236. Accordingly, conditions featured by disturbed
sleep with specificdeficit in slow wave sleep, as observed in
elderly people237, alcoholic238, and insomnia239 patients, show a
cytokine shift towards Th2. The balance of Th1/Th2 immunity
and its shift during sleep deprivation may have crucial implica-
tions in anti-microbial and anti-tumor immune responses. Th2
over-activity is known to be involved in some forms of allergic
responses, and to increase the susceptibility to infection240.
Likewise, regarding the anti-tumor immune action, Th1 response
supports cytotoxic lymphocytes and tumor cells destruction with
the potential of elimination or control of tumor cell growth, so
that a type 1 adaptive immune response (increased antigen pre-
sentation, IFN-γsignaling, and T-cell receptor signaling) may be
associated with an improved survival or prognosis241,242.In
contrast, Th2 over-response is thought to contribute to tumor
development and progression, by limiting cytotoxic T lympho-
cytes proliferation and by the modulation of other inflammatory
cell types241.
Several cellular and molecular signaling pathways may be
involved in mediating the influence of sleep deprivation on
immune and inflammatory functions (Fig. 3). Increased oxidative
stress markers and/or decreased antioxidant defense have been
found after sleep deprivation243–245. Sleep shows an antioxidant
function, responsible for eliminating reactive oxygen species
produced during wakefulness, and contrarily sleep deprivation
may cause oxidative stress, which leads to cell senescence,
unbalanced local/systemic inflammation, dysmetabolism, and
immune derangements246,247.
Effects of sleep deprivation on the immune response may
derive from the activation of the SNS with the corresponding
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increase in systemic catecholamines22,248. Catecholamines signal
to immune cells via adrenergic receptors, which are primarily α-
and β-adrenergic in myeloid cells and β-adrenergic in
lymphocytes249. The immune outcome of the sympathetic sig-
naling is complex, and includes both stimulatory and inhibitory
effects depending on cell and receptor types, cell development/
activation states, and local microenvironment249,250. Some evi-
dence suggest that β-adrenergic signaling inhibits and α-
adrenergic signaling promotes excessive inflammation under
endotoxemia250. Activation of α-adrenergic signaling in periph-
eral tissues induces the upregulation of pro-inflammatory
cytokines250,251. Sympathetic activation also suppresses the
transcription of type I IFNs (IFN-αand IFN-β) genes and
interferon response genes, which play a key role in anti-viral
immunity252, and inhibits via β-adrenergic signaling the anti-
tumor cytotoxicity of T lymphocytes253. In vitro β-adrenergic
stimulation repressed Th1 response and stimulated Th2 response,
with varying effects found in vivo249,254. Although the specific
role of SNS activation in the immune phenotype associated with
sleep deprivation is not clearly established, data suggest a pro-
inflammatory effect of SNS under sleep deprivation. Indeed,
chemical sympathectomy has been recently shown to alleviate the
inflammatory response following chronic sleep deprivation in
mice255, and both α- and, to a lesser extent, β-adrenergic recep-
tors seem to contribute to the sympathetic regulation of inflam-
matory responses to sleep deprivation256.
At the molecular levels, sleep deprivation led to significant gene
expression changes in animal tissues257–259 and human blood
monocytes203,233,260–262, with affected genes mostly related to
immune and inflammatory processes (leukocyte function, Th1/
Th2 balance, cytokine regulation, and TLR signaling), oxidative
stress, stress response, apoptosis, and circadian system, collec-
tively indicating immune activation and hyperinflammation.
Sleep loss and mistimed sleep also led in the blood tran-
scriptome to alteration and reduction in the circadian rhythmicity
of gene expression261,263, which is an integral part of basic bio-
logical processes and homeostasis264–266.
The activation of the pro-inflammatory NF-κB/Rel family of
transcription factors by sleep deprivation, first demonstrated in
the late 1990s in mice267, and subsequently widely
confirmed233,260,261,268–272, is one of the most consistent findings
regarding upstream transcriptional regulation. NF-κB induces the
expression of genes (e.g., cytokines/chemokines, growth factors,
receptors/transporters, enzymes, adhesion molecules) involved in
inflammation, immunity, proliferation, and apoptosis273, circa-
dian clock activity274, and sleep propensity275. Potential
signals for NF-κB activation under sleep deprivation include
increased adenosine levels, oxidative stress, altered metabolism
(adiposity and decreased insulin sensitivity), brain proteins/
metabolites (e.g., Aβ), melatonin suppression276, circadian clock
proteins277, and catecholamine surge due to increased sympa-
thetic activity278. Given the role of NF-κB in the pathophysiology
of inflammatory diseases273, its activation under sleep deprivation
may be a common pathway for the risk of morbidity and
mortality.
The intestinal microbiota is also affected by sleep loss279–281,
showing indices of dysbiosis (increased Firmicutes:Bacteroidetes
ratio; decreased diversity and richness), which may affect the
immune system282, and are similar to those associated with car-
diometabolic diseases45.
Fig. 2 Immune consequences of sleep deprivation. Sleep deprivation, as induced experimentally or in the context of habitual short sleep, has been found to
be associated with alterations in the circulating numbers and/or activity of total leukocytes and specific cell subsets, elevation of systemic and tissue (e.g.,
brain) pro-inflammatory markers including cytokines (e.g., interleukins [IL], tumor necrosis factor [TNF]-α), chemokines and acute phase proteins (such as
C reactive Protein [CRP]), altered antigen presentation (reduced dendritic cells, altered pattern of activating cytokines, etc.), lowered Th1 response, higher
Th2 response, and reduced antibody production. Furthermore, altered monocytes responsiveness to immunological challenges such as lipopolysaccharide
(LPS) may contribute to sleep deprivation-associated immune modulation. Hypothesized links between immune dysregulation by sleep deprivation and the
risk for immune-related diseases, such as infectious, cardiovascular, metabolic, and neurodegenerative and neoplastic diseases, are shown. The illustrations
were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. APC: antigen-
presenting cells.
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Countermeasures for sleep deprivation: effect on immune
parameters
Although the impact of strategies to improve sleep duration on
neurobehavioral performance and alertness after sleep depriva-
tion have been assessed283–285, sleep deprivation countermeasures
to improve immune and inflammatory parameters, and, corre-
spondingly, disease risk and outcomes have been studied to a
lesser extent.
Although extension of habitual short sleep did not show to
significantly counterbalance the immune consequence of sleep
deprivation286–288, mixed results derive from nighttime recovery
sleep following sleep deprivation (Table 1), with limited evidence
of effectiveness for specific immune parameters210,214, and mostly
after multiple consecutive nights of 8 h sleep recovery or with an
extended nocturnal sleep duration212,289.
Although daytime napping (<20 min) restores alertness, and
mental and physical performance without provoking sleep inertia
associated with longer nap290–292, the effects of a short nap on
immune/inflammatory parameters after sleep deprivation have
yet to be firmly established. Differently form population
studies293, laboratory studies found immune benefit from
nap218,289,294,295. Regarding immune-related clinical outcomes,
controversy exists, with studies finding no association296, inverse
associations297,298 or positive association296, and a J-shaped
relationship299–301 between napping and CV and metabolic dis-
eases or cancer events and mortality. Whether changes in
immune parameters could contribute to the associations between
napping and immune-related diseases remains unclear.
Among the strategies to recover sleep deprivation-induced
immune changes, cognitive behavior therapy improves sleep
outcomes in insomnia and lowers cellular and systemic inflam-
matory markers302,303, and the risk score composed of CV and
metabolic risk factors304. This highlights the potential role of
targeting sleep in reducing the inflammatory risk and the asso-
ciated chronic diseases.
Summary and concluding remarks
Sleep exerts immune-supportive functions and impairments of
the immune-inflammatory system are a plausible mechanism
mediating the negative health effects of sleep deprivation, and in
particular, its role in the risk and outcomes of chronic diseases
such as infections, CV, metabolic and autoimmune diseases,
NDDs, and cancer. Caution should be exercised in interpreting
cellular and molecular outcomes of sleep deprivation in experi-
mental studies conducted till now as a result of an independent
effect of sleep deprivation, because other factors may play a role,
including extended wakefulness-associated processes, other fea-
tures of sleep-wakefulness, their temporal and functional segre-
gation or methodologies of sleep manipulation.
Randomized controlled trials assessing the effect of treatment
of sleep deprivation on inflammatory immune dysfunction and/
or health outcomes are needed. Knowledge of inflammatory and
immunological signatures in response to sleep curtailment may
inform not only on the underlying molecular links, but also
contribute to refine risk profiles to be used for developing bio-
markers of sleep deprivation and sleep disturbance-related health
Fig. 3 Pro-inflammatory molecular pathways induced by sleep deprivation. A schematic model of potential mechanistic pathways linking sleep
deprivation and inflammatory immune activation is depicted. Sleep deprivation is associated with activation of the sympathetic nervous system and release
of norepinephrine and epinephrine into the systemic circulation, as well as to some extent with impaired hypothalamus-pituitary axis stimulation. These
neuromediators may act along with other potential stimuli accumulated following sleep deprivation including reactive oxygen species (ROS), adenosine,
metabolic waste products (e.g., β-amyloid) not cleared during normal sleep, gut microbiota dysbiosis leading to altered local and systemic pattern of
metabolic products, as well as with changes in the profile of neuro-endocrine hormones, such as prolactin, growth hormone, and altered circadian rhythm
of melatonin secretion. In immune cells located in the brain and the peripheral tissues, these stimuli may in concert trigger inflammatory activation, with
release of cytokines, chemokines, acute phase protein, etc. via the recruitment of transcriptional regulators of pro-inflammatory gene expression, mainly
nuclear factor (NF)-κB, and disturbing the circadian rhythmicity of gene expression of both clock genes and metabolic, immune and stress response genes
(see text for further detail). E: epinephrine; NE: norepinephrine; TLR: Toll-like receptor. Arrows indicate stimulation; lines indicate inhibition. The
illustrations were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.
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Table 1 Main human findings on the effects of recovery sleep on sleep deprivation-induced changes in immune and inflammatory parameters.
Subjects
(number and
age range
or mean)
Sleep
deprivation
protocol
Effect of sleep
deprivation on
immune parameters
compared with
baseline
Recovery sleep
protocol
Effect of recovery sleep
on immune parameters
compared with baseline
Effect of recovery sleep
on immune parameters
compared with sleep
deprivation
Reference
Healthy men and
women (n=20,
21–30 yrs)
64 h TSD ↑Granulocytes and
monocytes, NK cell
activity
1 Night (h sleep
not reported)
↑Granulocytes,
monocytes; =NK cell
activity
=Granulocytes;
↓monocytes;
↓NK cell activity
Dinges
et al.214
Healthy men
(n=32,
19–29 yrs)
2 Nights TSD or
4 nights
of REM SD
TSD: ↑total leukocytes,
neutrophils, CD4
T cells; REM SD: ↓IgA
3 Nights (8 h
sleep/night)
=Total leukocytes,
neutrophils; ↑CD4
T cells ↓IgA
ND Ruiz
et al.308
Healthy young
men (n=10,
21–29 yrs)
1 Night TSD During SD: ↑
monocytes,
lymphocytes, NK cells.
The day after SD:
↓lymphocytes,
NK cells
1 Night
(8 h sleep)
=Monocytes,
lymphocytes; ↓NK cells
ND Born
et al.210
Healthy men
(n=12, mean
age 29 yrs)
40 h TSD ↑Plasma E-selectin;
↑systolic BP, heart
rate; plasma
norepinephrine;
↓endothelium-
dependent and
-independent
vasodilation
1 Night
(8 h sleep)
↑Plasma ICAM-1, IL-6,
norepinephrine
ND Sauvet
et al.191
Healthy men
(n=31,
18–27 yrs)
1 Night with
2 h sleep
↑Total leukocytes,
neutrophils
1 Night of 8 h
sleep or 1 night
of 10 h sleep
8 h Recovery sleep: ↑
leukocytes, neutrophils;
10 h recovery
sleep: =leukocytes,
neutrophils
8 h Recovery
sleep: =leukocytes,
neutrophils; 10 h recovery
sleep: ↓leukocytes,
neutrophils
Faraut
et al.289
Healthy men
(n=19,
19–29 yrs)
5 Nights with
4 h sleep/night
↓NK cells;
↑B cells;
↑plasma CRP;
↑IL-17, IL-1β,IL-6
(PBMC mRNA);
↓TNF-α(PBMC
protein)
2 Nights (8 h
sleep/night)
=NK cells; =B cells; ↑
CRP, IL-17; =IL-1β, IL-6,
TNF-α
ND van
Leeuwen
et al.203
Healthy men
(n=9,
22–27 yrs)
5 Nights with
4 h sleep/night
↑Total leukocytes,
monocytes,
neutrophils,
lymphocytes
7 Nights (8 h
sleep/night)
↓Monocytes,
lymphocytes; ↑
neutrophils
ND Lasselin
et al.212
Healthy men and
women (n=24,
36-76 yrs)
1 Night with
4 h sleep
↑IL-6 and TNF-α
(PBMC protein)
1 Night
(8 h sleep)
↑IL-6 and TNF-αND Irwin
et al.262
Healthy men
(n=10,
22–37 yrs) (Exp.
1) and healthy
88 h TSD (Exp.
1) and 10 days
with 4.2 h
↑Plasma CRP 3 Nights
(assessment
only in the first
recovery day)
↑Plasma CRP ND Meier-
Ewert
et al.190
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outcomes, which may also represent potential targets of inter-
ventions. Recent metabolomic305 and transcriptomic306 studies
hold promise in biomarker discovery306.
These efforts may converge towards a new ground fostering
interactions between the sleep research and the medical com-
munity to translate scientific knowledge into the clinic, prioritize
health issues, and develop strategies and policies for subject risk
stratification, to include evidence-based sleep recommendations
in guidelines for optimal health and to address sleep hygiene at
the individual and the population levels, as a means to prevent the
negative health consequences of sleep deprivation. These actions
might also foster health literacy and empowerment of individuals
to actively better manage their own health and well-being
throughout their life course by means of lifestyle, nutritional, and
behavioral habits including sleep hygiene307.
Conclusively, in the perspective of staying healthy in this
rapidly changing society, the sleep–immunity relationship raises
relevant clinical implications for promoting sleep health and, as
evidenced here, for improving or therapeutically controlling
inflammatory response by targeting sleep. This may ultimately
translate, in the era of preventive medicine, into addressing sleep
as a lifestyle approach along with diet and physical activity to
benefit overall public health.
Reporting summary. Further information on research design is available in the Nature
Research Reporting Summary linked to this article.
Data availability
All data generated or analysed during this study are included in this published article.
Received: 12 January 2021; Accepted: 26 October 2021;
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Table 1 (continued)
Subjects
(number and
age range
or mean)
Sleep
deprivation
protocol
Effect of sleep
deprivation on
immune parameters
compared with
baseline
Recovery sleep
protocol
Effect of recovery sleep
on immune parameters
compared with baseline
Effect of recovery sleep
on immune parameters
compared with sleep
deprivation
Reference
men and women
(n=10,
26–38 yrs)
(Exp. 2)
sleep/night
(Exp. 2)
Healthy men and
women (n=21,
25–39 yrs and
n=49, 60-
84 yrs)
1 night with
4 h sleep
↑IL-6 and TNF-α
(PBMC protein) in
younger adults
1 night
(8 h sleep)
↑IL-6 and TNF-αND Carroll
et al.309
Healthy men and
women (n=30,
18–34 yrs)
6 Nights with
6 h sleep/night
↑Plasma IL-6 3 Nights (10 h
sleep/night)
=Plasma IL-6 ↓Plasma IL-6 Pejovic
et al.310
Healthy men and
women (n=14,
18–35 yrs)
5 Nights with
4 h sleep/night,
for 3 weeks
↑IL-6 (PBMC protein) 2 Nights (8 h
sleep/night), for
3 weeks
↑IL-6 (PBMC protein) ND Simpson
et al.234
BP blood pressure, exp experiment, ICAM-1 intercellular adhesion molecule-1, ND not determined, PBMC peripheral blood mononuclear cells, SD sleep deprivation, TSD total sleep deprivation, VCAM-1 vascular cell adhesion molecule-1, yrs years, ↑significant increase, ↓
significant decrease, =no significant change.
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Author contributions
E.S. reviewed the literature and wrote the manuscript draft. S.G. and P.L. contributed to
writing the manuscript and revised the manuscript draft. N.L.B. and N.M. reviewed the
final manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s42003-021-02825-4.
Correspondence and requests for materials should be addressed to Sergio Garbarino.
Peer review information Communications Biology thanks the anonymous reviewers for
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Montague-Cardoso. Peer reviewer reports are available.
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