preface
Sleep-immune interactions are a well-known phenomenon, and in everyday life, infections can make us feel tired and increase the desire to sleep, therefore, people usually recommend a good night's sleep as the "best drug" to treat infectious diseases.
Insomnia affects nearly a quarter of adults; it increases the risk of depression, inflammatory diseases and infectious diseases, and leads to death from a variety of causes. Therefore, it is important to understand the biological mechanisms associated with reducing insomnia. I write this article to better plan sleep and improve my quality of life.
The main content of the article is based on an article by Michael R. Irwin of the Institute of Neurology and Human Behavior at UCLA published by Nature Review Immunology in July 2019.
Sleep-related concepts
sleep
Sleep is a natural circulating state of arousal in the brain and body. It is characterized by: altered consciousness, reduced responsiveness to stimuli and inhibition of voluntary movement. Sleep cannot be detected by a single test and is generally measured by multiple physiological behavioral representations, including objective changes in electroencephalogram (EEG), changes in electromyography (EMG), or respiratory rate.
Sleep has multiple neurological functions, such as supporting changes in brain connectivity and associated regulatory mechanisms. Sleep helps keep a person emotionally and cognitively sharp, and also promotes physiological homeostasis and resilience.
Insomnia
Difficulty starting or maintaining sleep, early awakening, interruption or non-restorative sleep, and associated daytime dysfunction must be present for at least 3 nights per week and lasting 3 months or more.
Slow Wave Sleep (SWS)
The sleep phase, also known as deep sleep, static sleep, is characterized by: synchronized EEG with the presence of slow waves, or incremental wave activity. SWS is often seen as a time of rest. Most don't dream.
Rapid eye movement sleep (REM sleep)
A phase of sleep, also known as abnormal sleep, or dynamic sleep, is characterized by synchronizing EEG activity in a manner similar to that of wakefulness, accompanied by random and rapid movements of the eyes, accompanied by low muscle tone. This is accompanied by dreams.
Sleep and inflammation
Sleep normally
Sleep regulates the central nervous system, such as the hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS), while regulating the immune system.
Sleep and circadian rhythms affect the body's inflammatory state. For example, the circadian rhythm of IL-6 has a peak at 19:00 and 5:00 each, and nighttime sleep is required for IL-6, TNF, and TLR-4. Experimental sleep deprivation can cause insufficient nocturnal IL-6 secretion, inhibiting the production of TNF by mononuclear cells, but causing IL-6 to shift from nocturnal secretion to daytime hypersecretion.
Different stages of sleep have different regulatory effects on nocturnal changes in inflammatory cytokine activity. Although there are data showing that levels of inflammatory cytokines peak at night, dominated by SWS, higher levels of IL-6 have been reported in REM sleep, but no SWS. Nighttime IL-6 and SIL-6R levels increase with increased REM sleep levels, which correlate with TLR4-stimulated monocyte-generating IL-6 levels in the morning.
Activation of SNS is thought to promote the expression of inflammatory transcription profiles.
Sleep is a period of low metabolic demand. Therefore, the increase in sleep-induced inflammatory activity in the second half of the night is justified, which prepares the body for possible infections – in other words, during this quiescent period, they mediate the host's prepared defense response to the pathogen.
When an acute threat is perceived at the organism or cellular level (e.g., viral exposure or cellular stress), stress-induced sleep occurs, which increases sleep duration and further strengthens host resilience.
Sleep disorders
When the central nervous system feels a chronic, lasting threat for days to weeks, the sleep system undergoes maladaptive changes that become sleep disorders. Contemporary society, mainly human beings face social pressure, human-machine relationship pressure, etc., causing sleep continuation and sleep structure disorders (loss of SWS and prolongation of RAPID EYE movement sleep time). Sleep itself in turn affects the inflammatory state, with a change in the temporal distribution of inflammation and an increase in inflammatory factors occurring during the day rather than at night.
Partial sleep deprivation activates inflammatory signaling pathways, such as those involving NF-κB, AP-1, and STAT family proteins, which increase levels of mRNAs encoding pro-inflammatory cytokines and increase the production of IL-6 and TNF by TLR4-stimulated monocytes. Persistent sleep disturbances lead to the constant activation of the inflammatory response, which can cause damage to the host. Chronic inflammation is widely thought to be associated with several major diseases, including depression, certain cancers, cardiovascular disease, and Alzheimer's disease-related dementia.
Sleep with anti-infective immunity
Nighttime sleep, as well as physiological factors, enhance adaptive immunity to viruses through the distribution of immune cells in the body, as well as by enhancing the expression of antiviral cytokines. During normal sleep, antigen-presenting cells (APCs) and T cells are redistributed from the circulation and accumulate in lymphoid tissue.
Sleep promotes activation of T cells, producing IL-2 and IFN-γ, DC cells and mononuclear cells producing IL-12, inducing an adaptive immune response to the Th1 cell type. Sleep can also reduce the production of inhibitory IL-10.
When sleep is interfered with experimentally, T cells reduce IL-2 production, switch to Th2 cytokine activity, reduce monocyte production of IL-12 and increase IL-10 expression.
Reduced sleep reduces response to flu vaccines and the titer of protective antibodies.
Regarding the risk of infection, short-term sleep duration predicts pneumonia risk (nightly sleep
How sleep regulates immunity
Hypothalamic-pituitary-adrenal axis (HPA axis)
Circadian rhythms mainly regulate activity and sleep in the HPA axis. In the first half of the night, there is relatively a relatively high amount of short-wave sleep (SWS), which is also the period of the lowest HPA activity in 24 hours, including the release of hypothalamic adrenocorticotropic hormone releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenocorticotropic hormone (such as cortisol). ReM sleep is the mainstay in the second half of the night, and there is the strongest PHA activity when it is close to waking up.
Circadian rhythms and sleep regulate inflammatory activity, associated with transient release of cortisol at night and SWS sleep. During SWS, low levels of cortisol have a unique mechanistic role in promoting the antiviral immune response. When the binding of cortisol to glucocorticoid receptors in the blood is blocked, the interferon γ, IL-2, and TNF secreted by CD4 and CD8T cells increase.
Sleep disturbances, but not acute sleep deprivation, cause sustained activation of HPA, causing immune cell glucocorticoid resistance. Although the mechanism of glucocorticoid resistance is not fully understood, there is a potential mechanism that is thought to be the accumulation of inflammatory cytokines that promote the accumulation of major negative β subtypes of glucocorticoid receptors. In addition, psychological and physiological stress stimulates the expression of endogenous injury-associated molecular patterns (DAMP). DAMP activates the NLRP3 inflammasome, thereby inducing caspase-mediated glucocorticoid receptor breakage, leading to glucocorticoid resistance.
However, this mechanism has not been studied in connection with sleep disorders. The sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids is also regulated by polymorphic genetic variants encoding glucocorticoid receptors; alloelic variants of glucocorticoid sensitivity are associated with elevated IL-6 levels under short sleep conditions, which affects heterogeneity of inflammation risk levels in individuals with short sleep durations.
Sympathetic (SNS) regulation
During sleep, SNS activity decreases significantly, shifting from the sympathetic to parasympathetic or vagus nerves. SNS activity decreases during non-REM sleep and increases SNS activity during REM sleep. When sleep deprivation occurs, SNS activity increases throughout the night. Sympathetic outflow also increases in insomnia patients, and the level of norepinephrine and epinephrine in circulation increases, which is more pronounced when short sleep durations occur at the same time as insomnia, which is also associated with an increase in biomarkers of inflammation. Norepinephrine causes activation of NF-κB and expression of inflammatory genes through β-adrenergic receptors, as well as an increase in the production of inflammatory cytokines and systemic inflammation in the body.
Estimates of sympathetic activity—variability in heart rate from before, during NREM, and REM sleep—are associated with an increase in morning IL-6 levels. In addition, when sleep deprivation or insomnia causes an increase in SNS activity, natural killer (NK) cell activity decreases.
How immunity regulates sleep
Peripheral pro-inflammatory signals interact with the central nervous system (CNS), altering central nervous system activity and regulating sleep processes.
Neural mechanisms
Cytokines such as IL-1 and pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides, act on the vagus nerve, which projects onto multiple brain regions involved in sleep regulation, including solitary nucleus, bulbar ventral lateral nucleus, hypothalamic paraventricular and superorditial nuclei, and amygdala nuclei. Vagus nerve cutting has been reported to block the induction of sleep by systemic cytokines and the expression of cytokine mRNAs in the brain induced by systemic cytokines.
Hormonal mechanisms
There are macrophages expressing Toll-like receptors (TLRs) in many parts of the central nervous system. When these macrophages are activated by PAMPs, inflammatory cytokines such as IL-1 are produced, which can spread into the brain through volume. In addition, endothelial cells express IL-1 receptors, which are activated by circulating IL-1, leading to the production of local prostaglandin e2, triggering immune activation within the brain.
Blood-brain barrier transport mechanism
The blood-brain barrier (BBB) actively transmits multiple immunomodulatory molecules in the central nervous system, a process that is actively coordinated by the central nervous system, unlike the passive spread or dysfunction of BBB that leaks out unregulated.
Sleep and circadian processes regulate the active transport mechanisms of BBB. In addition, the function of BBB has also changed due to infection and age, which may contribute to the active transport of IL-1, IL-6, and TNF. Changes in sleep patterns in these cases further increase the transport of inflammatory mediators at the blood-brain barrier.
Cellular mechanisms
When immune cells (usually monocytes) are activated, they can be connected to the brain's vasculature and other vasculatures. Peripheral inflammatory signals stimulate microglia to produce CCL2 (MCP1), which further attracts monocytes to the brain. Astrocytes stimulated by cytokines can also produce CCL2 to attract immune cells to the brain.
Clinical impact
Aging of organisms
Sleep disorders and death are associated with aging and may have a lot to do with inflammation. Overnight sleep deprivation causes changes in the transcription profile of surrounding mononuclear cells, increased expression of genes associated with DNA damage and cellular senescence (such as the senescent signal marker CDKN2A (also known as p16INK4A), which inhibits the progression of the cell cycle. Sleep disorders are associated with another biological marker of cell aging, namely shortening of the length of white blood cell telomeres, and epigenetic methylation of female DNA (called epigenetic age). Epigenetic age can be used to predict age-related morbidity and mortality.
Cognitive aging
In meta-analyses alone, sleep disorders have been reported to predict cognitive aging. Extreme sleep duration (≤5 hours per night or ≥9 hours per night) was associated with impaired cognitive function in older adults compared to control sleep time (7 hours per night), and sleep disturbances were associated with an increased risk of all etiological dementias, including Alzheimer's disease and vascular-induced dementia.
Changes in activated microglia function, including phagocytosis, extension of microglial processes to tissue damage, amyloid clearance, including impairment of phagocytosis. Each of these processes individually and together contributes to the progression of Alzheimer's pathology.
The interaction between activated microglia phenotype and inflammation leads to a feed-forward cycle, which activates microglia leading to the accumulation of amyloid, which increases inflammation, which leads to more activation of microglia, which accelerates the accumulation of Alzheimer's disease pathology.
depression
Sleep disorders are one of the most common symptoms in people with depression and a strong predictor of depression recurrence. Innovative therapies that target the mind and body, such as mind-body interventions such as tai chi and meditation, are becoming strategies to reduce symptoms of insomnia and reverse inflammation, reduce the severity of depression, and may also help prevent depression.
Meow Comments:
Various factors (physical, mental, work, etc.), maintaining adequate and high-quality sleep, have become a major problem in our lives.
Normal sleep allows the body to secrete inflammatory factors at night, which is of great significance for anti-infection.
However, if sleep is impaired or deprived, the nocturnal inflammatory activity becomes the inflammatory activity of the day, which will cause inflammatory diseases of the body, including cardiovascular, diabetic, and even blood tumors, depression, accelerated Alzheimer's disease, etc.
bibliography
Michael R. Irwin，Sleep and inflammation:partners in sickness and in health，Nature Reviews Immunology, 19,pages702–715(2019)
Prather, A. A. & Leung, C. W. Association of unsufficient sleep with respiratory infection among adults in the United States. JAMA Intern. Med. 176,850–852 (2016).