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Cited by 624Sleep and Wakefulness ResearchSleep and related disordersCircadian rhythm and melatonin

Sleep health: Reciprocal regulation of sleep and innate immunity

Open access
Irwin, Michael R, Opp, Mark R·2017·Neuropsychopharmacology
DOI 10.1038/npp.2016.148PMC PMC5143488
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Abstract

Sleep disturbances including insomnia independently contribute to risk of inflammatory disorders and major depressive disorder. This review and overview provides an integrated understanding of the reciprocal relationships between sleep and the innate immune system and considers the role of sleep in the nocturnal regulation of the inflammatory biology dynamics; the impact of insomnia complaints, extremes of sleep duration, and experimental sleep deprivation on genomic, cellular, and systemic markers of inflammation; and the influence of sleep complaints and insomnia on inflammaging and molecular processes of cellular aging. Clinical implications of this research include discussion of the contribution of sleep disturbance to depression and especially inflammation-related depressive symptoms. Reciprocal action of inflammatory mediators on the homeostatic regulation of sleep continuity and sleep macrostructure, and the potential of interventions that target insomnia to reverse inflammation, are also reviewed. Together, interactions between sleep and inflammatory biology mechanisms underscore the implications of sleep disturbance for inflammatory disease risk, and provide a map to guide the development of treatments that modulate inflammation, improve sleep, and promote sleep health.

AI snapshot

Written from the paper’s full text.

TL;DR

This review integrates evidence that sleep disturbance and innate immune/inflammatory biology are reciprocally linked: sleep loss activates inflammatory signaling, and inflammatory mediators regulate sleep. It also outlines clinical implications for depression, inflammaging, and behavioral insomnia treatments that may reduce inflammation.

Key findings

  • A meta-analysis of 72 studies found sleep disturbance associated with higher CRP (ES .12; 95% CI 0.05–0.19) and IL-6 (ES .20; 95% CI 0.08–0.31). Shorter sleep duration was associated with higher CRP (ES .09; 95% CI 0.01–0.17) but not IL-6; long sleep duration was associated with higher CRP (ES .17; 95% CI 0.01–0.34) and IL-6 (ES .11). Neither sleep disturbance nor sleep duration was associated with TNF, though power was low (672 participants).
  • Experimental sleep deprivation did not significantly alter circulating CRP, IL-6, or TNF in healthy adults in meta-analysis, but acute sleep loss activated upstream cellular and genomic inflammatory signaling, including increased monocyte TLR-4 responses, NF-κB, IL-6/TNF transcription, STAT1/STAT5, and DNA damage response/senescence markers such as p16INK4a.
  • Bidirectional immune regulation of sleep is supported: IL-1 and TNF promote NREM sleep, and TNF antagonism (infliximab) reduced spontaneous arousals and increased sleep efficiency in treatment-resistant depression, correlating with reduction in soluble TNF receptor 1.
  • Behavioral insomnia treatment with CBT-I and Tai Chi improved sleep and reduced inflammation; insomnia remission was associated with 50% lower high CRP one year after treatment, and CBT-I reversed activation of NF-κB, AP-1, and CREB inflammatory signaling pathways.

Methods

  • Narrative review/overview synthesizing human experimental sleep deprivation, naturalistic/epidemiological, animal, clinical/translational, and intervention studies.
  • Includes a meta-analysis of 72 studies, with nearly 34,000 participants for CRP and over 3,000 for IL-6.
  • No new primary data; the paper qualitatively integrates reported effect sizes and mechanistic pathways, including SNS, HPA axis, and conserved transcriptional response to adversity (CTRA).

Limitations

  • Stated: human sleep–innate immunity studies are constrained because measures focus almost exclusively on circulating inflammatory markers or ex vivo cell activation; it is unknown whether sleep alters innate immunity in other compartments including the brain; most studies use one or two measures at a single time point; many examine either circulating markers or stimulated cytokine expression but not both; anti-inflammatory cytokines such as IL-10 are often not assessed.
  • Stated: mechanisms explaining sleep disturbance–inflammation associations are relatively unexplored; most naturalistic studies rely on self-report, with a relative absence of quantitative polysomnography; heterogeneity arises from differences in sleep assessment.
  • Evident: as a narrative review, conclusions rely on heterogeneous designs and cannot establish causality; many cited experimental studies have small samples and mixed results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/npp.2016.148

Cites

254 of 254 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 307 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In healthy adults, our meta-analysis found no significant effect of total, partial, or restricted sleep deprivation on CRP, IL-6, or TNF markers.

    “our recent meta-analysis did not find any significant effect of sleep deprivation, inclusive of total-, partial, and sleep restriction, on markers of CRP, IL-6, and TNF in healthy adults (Irwin et al, 2016)”
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    • cites Irwin et al, 2016 source

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  • Findingreasoning

    The effect size linking sleep disturbance with IL-6 was larger than that for CRP.

    “Finally, it is not surprising that the ES linking sleep disturbance with IL-6 were larger than those found for CRP.”
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    • cites Irwin et al, 2016 source

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  • Findingcitation

    Meta-analytic findings found long sleep duration, but not short sleep duration, associated with increased CRP and IL-6.

    “Meta-analytic findings have also examined extremes of sleep duration, and found that long sleep duration, but not short sleep duration, were associated with increase in CRP and with increase in IL-6 (Irwin et al, 2016).”
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  • Findingcitation

    Shorter sleep duration, but not the extreme short-sleep category, was associated with higher CRP (ES 0.09; 95% CI 0.01-0.17).

    “Shorter sleep duration, but not the extreme category of short sleep, was associated with higher levels of CRP (ES.09; 95% CI = 0.01-0.17)”
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    • cites Irwin et al, 2016 source

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  • Findingcitation

    Extreme long sleep duration was associated with higher IL-6 (ES 0.11; 95% CI 0.02-20).

    “and IL-6 (ES.11; 95% CI = 0.02-20).”
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  • Classified as probably not a substantial claim. 13

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    Findingcitation

    Sex differences were statistically significant only for sleep disturbance predicting IL-6 and continuous sleep duration predicting CRP.

    “However, these sex differences were only statistically significant for sleep disturbance predicting IL-6 and sleep duration continuously predicting CRP.”
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    Findingcitation

    Effect sizes linking sleep disturbance to inflammation are comparable to, and sometimes larger than, effects of some demographic and biobehavioral factors on inflammation.

    “The ES linking sleep disturbance to inflammation are comparable, and larger in some cases, than the effects of some demographic and other biobehavioral factors on inflammation.”
    Quote in the paperSubstantial claim

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    Findingcitation

    Neither sleep disturbance nor sleep duration was associated with TNF, though low statistical power with 672 participants tempers this conclusion.

    “Neither sleep disturbances nor sleep duration was associated with TNF, although this conclusion is tempered by low statistical power with only 672 participants.”
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    • cites Irwin et al, 2016 source

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    Findingcitation

    When sleep disturbance was assessed with more robust validated measures, increases in CRP and IL-6 were found; single-question symptom reporting yielded mixed effects.

    “when sleep disturbance was assessed using more robust and validated measures, increase in CRP and IL-6 was found.Yet, when assessment was by simple symptom reporting with reliance on only a single question, there were mixed effects”
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    Findingcitation

    Cytokine levels were more strongly correlated with depressed mood in females with sleep disturbance, despite similar overall increases in circulating proinflammatory cytokines in females with and without sleep disturbance.

    “cytokine levels were more strongly correlated with depressed mood in females with sleep disturbance, despite similar overall increase in circulating proinflammatory cytokines in females with and without sleep disturbance”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cho et al, 2016

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    Findingcitation

    CBT-I reduced risk of being in the high-risk group at 4 months and at 16 months, whereas TCC reduced risk at 16 months.

    “CBT-I reduced risk of being in the high-risk group at 4 months and at 16 months, whereas TCC reduced the risk at 16-months.”
    Quote in the paperSubstantial claim

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    Findingown data

    The reduction of cellular inflammation induced by TCC was maintained during follow-up at 7 and 16 months, even though improvements in sleep disturbance were not maintained in the long term.

    “Interestingly, the reduction of cellular inflammation induced by TCC was maintained during follow-up at 7 and 16 months, even though improvements in sleep disturbance were not maintained in the long term”
    Quote in the paperSubstantial claim

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    Premisecitation

    Insomnia and other sleep disturbances are independent contributors to the risk of inflammatory disorders and major depressive disorder.

    “Sleep disturbances including insomnia independently contribute to risk of inflammatory disorders and major depressive disorder.”
    • Also stated in: § INTRODUCTION · boosted
      “insomnia is not only a health complaint but also independently contributes to risk of infectious and inflammatory disease including depression, as well as all-cause mortality (Irwin, 2015).”
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    • cites Irwin, 2015

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    Premisecitation

    About 25% of Americans have sleep problems, and almost 33% of adults report at least one insomnia complaint.

    “Over one-quarter of the population of the United States experience sleep problems, and nearly a third of adults experience at least one insomnia complaint (Ohayon, 2002).”
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    Premisecitation

    Innate immunity is the body's initial defense against infection and tissue damage.

    “Innate immunity serves as the body's first line of defense against tissue damage and microbial infection (Medzhitov, 2008).”
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    • cites Medzhitov, 2008 source

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    Premisecitation

    After detecting a foreign challenge, innate immune cells activate within minutes to hours and start inflammatory processes that contain infection and aid healing.

    “Within minutes to hours after recognition of a foreign challenge, these cells become activated, which initiates a cascade of inflammatory processes that help contain an infection and ultimately promote healing and recovery (Medzhitov, 2008).”
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    Premisecitation

    Sleep deprivation does not abolish a brief IL-6 peak at 0100 hours, showing ongoing circadian control of IL-6.

    “even during this time of sleep deprivation, a transient peak in IL-6 occurs at 0100 hours indicating that circadian factors continue to influence IL-6 levels (Redwine and Hauger et al, 2000)”
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    • cites Redwine and Hauger et al, 2000

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    Premisecitation

    IL-6R rises most in the late night, matching evidence that IL-6 is high then and REM sleep is relatively increased.

    “the increase in IL-6R is most pronounced during the late part of the night (Dimitrov and Lange et al, 2006), consistent with evidence that IL-6 levels are prominently increased during the late part of the night, along with relative increase in REM sleep amounts (Redwine and Hauger et al, 2000).”
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    • cites Dimitrov and Lange et al, 2006

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    • cites Redwine and Hauger et al, 2000

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    Study design and conductcitation

    Actigraphy reliably estimates sleep continuity and correlates with polysomnography on total sleep time, efficiency, and wake after sleep onset.

    “actigraphic estimates of sleep continuity are reliable and correlate with measures of total sleep time, sleep efficiency, and wake after sleep onset as characterized by polysomnography (Ancoli-Israel et al, 2003)”
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    • cites Ancoli-Israel et al, 2003 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Insomnia ranks among the most common complaints in psychiatric groups, including adults with major depressive disorder, and appears in 50-70% of primary care patients.

    “insomnia is one of the most ubiquitous complaints in psychiatric populations, including adults with major depressive disorder (Irwin, 2015) and is reported in 50-70% of primary care patients (Shochat et al, 1999;Wittchen et al, 2001,Tubtimtes et al, 2009).”
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    • cites Irwin, 2015

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    • cites Shochat et al, 1999

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    • cites Wittchen et al, 2001

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    Premisecitation

    Toll-like receptors are found on macrophages, neutrophils, and dendritic cells and represent one class of pattern recognition receptors.

    “Toll-like receptors (TLRs), found on macrophages, neutrophils, and dendritic cells, represent one class of PRRs (Medzhitov, 2008).”
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    • cites Medzhitov, 2008 source

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    Premisecitation

    LPS binding to TLR4 triggers a conserved cascade that activates transcription factors NF-κB and AP-1.

    “endotoxin or lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, binds to TLR4 (Medzhitov, 2008), which initiates a conserved signaling cascade that is characterized by activation of key intracellular transcription factors such as nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) (Karin, 2006).”
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    • cites Medzhitov, 2008 source

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    • cites Karin, 2006

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    Premisecitation

    Both sleep disturbance and inflammation contribute to depression.

    “sleep disturbance and inflammation are both thought to have a role in depression (Irwin, 2015).”
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    • cites Irwin, 2015

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    Study design and conductcitation

    The Pittsburgh Sleep Quality Index uses a cutoff with high sensitivity and specificity for clinically significant sleep impairment.

    “a threshold score shows high sensitivity and specificity for identifying clinically significant sleep impairment (Cole and Motivala et al, 2006).”
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    • cites Cole and Motivala et al, 2006

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    Interpretationnone given

    Sleep importantly shapes innate immune dynamics; sleep disturbance can upregulate innate immunity, shown by higher cellular and genomic inflammation markers.

    “sleep has an important role in the dynamics of innate immune responses including the effects of sleep disturbance to upregulate innate immune responses, as indexed by increases in cellular and genomic markers of inflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Insomnia Severity Index has high sensitivity and specificity for detecting insomnia cases.

    “the sevenitem Insomnia Severity Index, which assesses sleep quality, fatigue, psychological symptoms, and quality of life, with a high sensitivity and specificity for the detection of insomnia cases (Morin et al, 2011).”
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    • cites Morin et al, 2011 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The innate immune system's circulating cells include monocytes, macrophages, and dendritic cells, which use invariant receptors to detect many pathogens.

    “Monocytes, macrophages, and dendritic cells comprise the immune cell types of the innate immune system, and these cells circulate in the body using invariant receptors to detect a wide variety of pathogens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Medzhitov, 2008 source

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    Premisecitation

    Some single items forecast daytime impairment, which is required for an insomnia diagnosis.

    “certain single items predict daytime consequences, a necessary criterion for the diagnosis of insomnia (Kierlin et al, 2012).”
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    • cites Kierlin et al, 2012

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    Premisecitation

    Chronic circadian disruption increases inflammatory gene expression profiles in adipose tissue, possibly due to disruption in the circadian clock gene Rev-erbalpha.

    “along with an increase in inflammatory gene expression profiles in adipose tissue (Herrero et al, 2015) possibly due to disruption in the circadian clock gene Rev-erbalpha (Sato et al, 2014).”
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    • cites Sato et al, 2014

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    Premisecitation

    The nighttime rise in TNF and its soluble receptor is mainly circadian, though some evidence links TNF to sleep rather than circadian factors.

    “In contrast to IL-6, nocturnal increase in tumor necrosis factor-α (TNF) and its soluble receptor appear to be driven primarily by circadian factors (Born et al, 1997), although there is evidence that sleep, but not circadian factors, is associated with TNF.”
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    • cites Born et al, 1997

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    Premisecitation

    A 2-hour nap seems protective and can reverse the IL-6 rise after four nights of restricted sleep.

    “a 2 h nap appears to be protective and reverses elevated levels of IL-6 following 4 nights of sleep restriction (Vgontzas et al, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vgontzas et al, 2007

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    Premisecitation

    Age modulated the effects of partial sleep deprivation: younger adults showed increased inflammatory cytokine production, whereas older adults did not.

    “Carroll et al (2015) found that age modulated the effects of partial sleep deprivation, such that younger adults had an increase in inflammatory cytokine production that was not present in older adults (Carroll et al, 2015).”
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    • cites Carroll et al, 2015

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    Premisecitation

    In RA patients and controls, greater TLR-4-stimulated monocytic TNF at 2300 h correlated with less wake after sleep onset and better sleep efficiency.

    “higher levels of TLR-4 stimulated monocytic production of TNF at 2300 hours were associated with decrease in awake time after sleep onset and with increase in sleep efficiency.”
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    • cites Bjurström et al, 2016

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    Premisenone given

    There is considerable variability in effect sizes between studies, with many relying on small samples.

    “there is considerable variability in effect sizes (ES) between the various studies with many studies relying on small samples.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The monocyte TLR-4 response to sleep loss was stronger in females than males, and females had sustained elevations in proinflammatory cytokine production throughout the following day.

    “Subsequent research demonstrated that this response was more robust in females, as compared with males, and that females showed sustained elevations in production of proinflammatory cytokines throughout the day following sleep loss.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Growth hormone and prolactin enhance proliferation and differentiation of T cells and promote type 1 cytokine activity.

    “Both of these neuroendocrine hormones are known to enhance the proliferation and differentiation of T cells as well as to promote type 1 cytokine activity (Lange et al, 2006;Besedovsky et al, 2012).”
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    • cites Lange et al, 2006

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    • cites Besedovsky et al, 2012

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    Premisecitation

    Higher spontaneous and stimulated IL-6 at 2300 hours was associated with increased stage 3 and SWS, with evidence that stage 4 was associated with decreases in IL-6 production at 0800 hours.

    “higher levels of spontaneous-and stimulated production of IL-6 at 2300 hours were associated with increase in stage 3 and SWS, with evidence that stage 4 was associated with decreases in IL-6 production at 0800 hours (Figure 2).”
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    • cites Bjurström et al, 2016

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    Interpretationreasoning

    Sleep loss may raise the risk of inflammatory disorders in younger adults by increasing cellular inflammation, while in older adults it may raise infectious disease risk through blunted TLR activation.

    “Such age-related differential effects suggest that sleep loss might contribute to risk of inflammatory disorders in younger adults by increasing cellular inflammation, whereas in older adults, sleep loss might increase the risk of infectious disease due to blunted TLR activation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Seven nights of restricted sleep raise plasma IL-6 in both sexes, TNF only in men, and inflammatory transcripts for IL-1β, IL-6, and IL-17, with the transcript rise persisting after recovery sleep.

    “even shorter periods of sleep restriction (ie, 7 nights) induce increase in plasma concentrations of IL-6 in men and women, increase of TNF in men only (Vgontzas et al, 2004), and increase in inflammatory transcripts of IL-1β, IL-6, and IL-17 (van Leeuwen et al, 2009), which persists even after a night of recovery sleep (van Leeuwen et al, 2009).”
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    • cites Vgontzas et al, 2004

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    Premisenone given

    Proinflammatory cytokines reach their peak in early slow-wave-sleep-dominated sleep, when growth hormone and prolactin are released.

    “proinflammatory cytokines peak during the early SWS-dominated portion of sleep, and SWS sleep is associated with the release of growth hormone (GH) and prolactin.”
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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This contrasts sharply with studies of upstream cellular and genomic inflammation pathways.

    “which stand in sharp contrast with findings that have evaluated upstream pathways of cellular and genomic markers of inflammation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Sleep at night boosts stimulated monocytic TNF production, suggesting nighttime sleep aids defense against microbes.

    “the enhancing effect of nocturnal sleep on stimulated monocytic TNF production adds to the notion that nocturnal sleep favors immune defense to a microbial challenge (Besedovsky et al, 2012).”
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    • cites Besedovsky et al, 2012

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    Premisecitation

    Partial-night deprivation and chronic sleep restriction model the sleep-duration problems common in depressed patients, so these experiments have translational value.

    “Partial night sleep deprivation and chronic sleep restriction are thought to mimic disturbances of sleep duration, which are ubiquitous in clinical populations such as depressed patients; hence, these experimental studies have translational implications in understanding the pathways by which inflammatory disease risk is elevated in persons with chronic sleep disturbance (Irwin, 2015).”
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    • cites Irwin, 2015

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    Premisecitation

    Sleep fragmentation is not routinely used experimentally, despite reduced sleep efficiency and more wake after sleep onset being common in depressed and older adults.

    “sleep fragmentation has not been systematically used as an experimental approach, even though loss of sleep efficiency and increase in wake after sleep onset are particularly prevalent in depressed patients and in older adults (Dew et al, 1996).”
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    • cites Dew et al, 1996

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    Interpretationcitation

    Females and socially isolated individuals may be at greatest risk and most likely to benefit from prevention approaches.

    “Taken together, these data suggest that females and those who feel socially isolated may be at greatest risk and are most likely to benefit from prevention approaches (Cho et al, 2015).”
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    • cites Cho et al, 2015

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    Premisecitation

    Restricted sleep activates transcriptional pathways and increases transcription of IL-6 and TNF.

    “Transcriptional pathways are also activated following a night of restricted sleep, with evidence of increaes in transcription of IL-6 and TNF (Irwin and Wang et al, 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Irwin and Wang et al, 2006 source

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    Premisecitation

    Self-reported poor sleep quality correlated with CRP and IL-6 at a magnitude comparable to age, but less than BMI.

    “Christian (Christian et al, 2011) found that self-reported poor sleep quality was correlated with CRP and IL-6 at a magnitude comparable to that between age and these markers of inflammation, but less than that found between BMI and CRP or IL-6”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Christian et al, 2011

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    • cites Friedman et al, 2005 source

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    Interpretationreasoning

    Because IL-6 induces CRP, sleep disturbance may have proximal effects on IL-6, with CRP increases appearing only when sleep disturbance is more persistent or severe.

    “It is known that IL-6 induces CRP; hence, sleep disturbance might have proximal effects on IL-6 and increase of CRP is found only when sleep is more persistent or more severe.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IL-6 induces CRP.

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    Premisecitation

    Elevated CRP associated with sleep disturbance was greater than that associated with sedentary physical activity, low socioeconomic status, and tobacco smoking, but not greater than BMI.

    “Liukkonen et al (2007) showed that elevated levels of CRP found in association with sleep disturbance (ie, self-reported problems sleeping) were greater than elevated levels associated with sedentary physical activity, low socioeconomic status, and tobacco smoking, but not with elevated body mass index.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liukkonen et al, 2007

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    Interpretationown data

    Sleep deprivation increases the DNA damage response, SASP expression, and pathways initiating cellular senescence in aged adults.

    “Together, sleep deprivation increases the DDR, increases senescenceassociated secretory phenotypic expression pattern, and promotes pathways involved in the initiation of cellular senescence in aged adults.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Experimental activation of inflammation activates brain sites regulating positive and negative affect and is associated with increased depressed mood, especially in women.

    “experimental activation of inflammation activates brain sites that regulate positive and negative effects (Eisenberger et al, 2009(Eisenberger et al, , 2010a(Eisenberger et al, , 2010b)), and is associated with increase in depressed mood, especially in women.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Eisenberger et al, 2009 source

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    • cites Eisenberger et al, 2010a

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    Premisecitation

    Patel et al found each additional hour of sleep duration associated with increased CRP and IL-6, while shorter sleep duration was associated with increased TNF.

    “Patel et al (2009) found that each additional hour of sleep duration resulted in an increase in CRP and an increase in IL-6, whereas a shorter sleep duration was associated with an increase in TNF.”
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    • cites Patel et al, 2009

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    Interpretationcitation

    Sleep loss activates inflammation and inflammatory signaling, and self-reported sleep disturbance is associated with increased inflammation.

    “Sleep loss activates inflammation and inflammatory signaling, and self-reported sleep disturbance (ie, insomnia complaints) is associated with increase in inflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Molecular causes of physical aging are thought to occur through accumulation of cellular damage to mitochondrial DNA, telomeric ends, coding-DNA, and proteins.

    “The molecular causes of physical aging are thought to occur through the accumulation of cellular damage to mitochondrial DNA (mtDNA), telomeric ends, coding-DNA, and proteins (Kennedy et al, 2014).”
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    • cites Kennedy et al, 2014 source

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    Premisecitation

    Sleep loss increased expression of genes in the composite DNA damage response, and this elevation persisted after recovery sleep.

    “there was evidence that the sleep loss induced increase in genes associated with the composite DNA damage response (DDR), and this elevated expression remained elevated after recovery sleep.”
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    • cites Carroll et al, 2016

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    Premisecitation

    Following one night of partial sleep loss, SASP gene expression and NFKB2 and NFKB1 increased, with NFKB2 remaining elevated after recovery sleep.

    “Following a single night of partial sleep loss, gene of the secretory-associated senescent phenotype was elevated, and increase was also found for NFKB2 and NFKB1, in which NFKB2 remained elevated even after a night of recovery sleep.”
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    • cites Carroll et al, 2016

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  • May combine two claims.

    Premisecitation

    Long sleepers (>8 h) have 30% greater mortality risk and short sleepers (<7 h) have 12% greater risk than those sleeping 7-8 h.

    “long sleepers (48 h per night) have a 30% greater risk, whereas short sleepers (o7 h per night) have a 12% greater risk of dying than those who sleep 7-8 h per night (Youngstedt and Kripke, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Youngstedt and Kripke, 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Delta sleep ratio was inversely associated with increase in depressive symptoms, and elevated alpha power was also associated, in patients treated with IFN-alpha for hepatitis C.

    “the delta sleep ratio (an index of early-night restorative delta power) was inversely associated with increase in depressive symptoms, as was elevated alpha power (8-12 Hz) in patients treated with IFN-alpha for hepatitis C.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lotrich and Germain, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When insomnia or persistent sleep disturbance occurs, it instigates depressive symptoms and predicts depression incidence.

    “when insomnia or persistent sleep disturbance occurs, it has a role in instigating depressive symptoms, and also predicts depression incidence (Ford and Kamerow, 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ford and Kamerow, 1989 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adrenergic signaling suppresses antiviral type I interferon genes and upregulates IL1B, TNF, and IL6, increasing systemic inflammatory activity.

    “Such adrenergic signaling suppresses transcription of antiviral type I interferon genes, as previously discussed elsewhere (Cole et al, 1998), and also upregulates transcription of the proinflammatory immune response genes IL1B, TNF, and IL6, leading to increase in systemic inflammatory activity (Cole, 2010).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cole et al, 1998 source

      Not checked in the free run.

    • cites Cole, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sleep disturbance may increase vulnerability to depression by augmenting affective sensitivity to cytokines and possibly altering neural sensitivity to inflammation.

    “which suggest that sleep disturbance may increase the vulnerability to depression by augmenting affective sensitivity to cytokines and possibly by altering neural sensitivity to inflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During NREM or SWS, sympathetic activity decreases markedly, whereas REM sleep has SNS outflow that is higher and similar to daytime levels.

    “during NREM or SWS, there is a marked decrease in sympathetic activity, whereas REM sleep is associated with SNS outflow that is higher and similar to daytime levels (Somers et al, 1993).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Somers et al, 1993

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clinical and experimental observations support a two-hit model of depression in which sleep disturbance is a vulnerability factor and later heightened inflammatory states trigger increased depressive symptoms.

    “These clinical and experimental observations support a 'two-hit' model of depression, one that posits that sleep disturbance serves as a vulnerability factor and that subsequent exposure to heightened inflammatory states such as an infectious challenge or psychological stress triggers increase in depressive symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sleep disturbance causes sympathetic activation, as experimental sleep deprivation induces similar increases in sympathetic markers.

    “it appears that sleep disturbance causes such sympathetic activation, as experimental sleep deprivation induces a similar increase in markers of sympathetic activity”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Irwin and Thompson et al, 1999

      Not checked in the free run.

    • cites Irwin and Ziegler, 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increases in urinary catecholamine and metabolite levels are more likely in insomnia patients with short sleep duration, similar to greater inflammatory biomarker activation in this severe phenotype.

    “increase in urinary catecholamine and levels of their metabolites are more likely to occur in those insomnia patients who also report short sleep duration, a pattern similar to the greater activation of inflammatory biomarkers in this more severe phenotype”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vgontzas et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Communication from the peripheral immune system to the CNS occurs by direct neural innervation, humoral mediators, and active transport across the blood-brain barrier.

    “Communication from the peripheral immune system to the CNS occurs by several mechanisms, including direct neural innervation, actions of humoral mediators, and by active transport systems that move substances across the blood-brain barrier (BBB)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dantzer et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sleep disturbance is a predictor of depression risk, possibly due to related increases in inflammation.

    “Given the role of sleep disturbance as a predictor of depression risk (Cho et al, 2008(Cho et al, , 2016;;Lee et al, 2013), possibly due to related”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cho et al, 2008

      Not checked in the free run.

    • cites Cho et al, 2016

      Not checked in the free run.

    • cites Lee et al, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glucocorticoid inhibition of immune response gene transcription is mediated by at least three mechanisms: promoter binding, GR-induced antiinflammatory genes inhibiting NF-κB, and protein-protein interactions antagonizing transcription.

    “The inhibitory effects of glucocorticoid activation on immune response gene transcription is mediated by at least three mechanisms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Irwin and Cole, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortisol binding affinity in humans is about tenfold higher for MR than GR, and about 70-80% of MR are continuously occupied throughout the 24-hour cycle.

    “Binding affinity of cortisol in humans is about tenfold higher for MR than GR (de Kloet et al, 1994); hence, about 70-80% of MR are continuously occupied throughout the 24hour cycle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites de Kloet et al, 1994

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prolactin and GH secreted during sleep have a role in immune regulation, though their effects have been studied mainly in relation to type 1 cytokines and adaptive immunity.

    “Prolactin and GH secreted during sleep also have a role in the regulation of the immune system, although their effects have predominantly been studied in relation to the production of type 1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Besedovsky et al, 2012

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    During early SWS-rich sleep, CRH, ACTH, and adrenal corticosteroids reach a minimum; later during REM-rich sleep, HPA secretory activity reaches a maximum around morning awakening.

    “During the early SWS-rich part of nocturnal sleep, release of hypothalamic corticotropin-releasing hormone (CRH), of pituitary corticotropin (ACTH) and of adrenal corticosteroids, reaches an absolute minimum; later during the night REM sleep-rich part of sleep, HPA secretory reaches a maximum at about the time of morning awakening.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Bidirectional communication exists between the CNS and peripheral immune system and is actively driven in response to insults.

    “Thus, bidirectional communication exists between the CNS and the peripheral immune system that is actively driven in response to a variety of insults.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sleep disruption increases blood-brain barrier transport of TNF in aged mice, but not in young mice.

    “sleep disruption increases BBB transport of TNF in aged mice, but not in young mice (Opp and Krueger, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Opp and Krueger, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with major depressive disorder show flatter diurnal cortisol slopes, with higher overall cortisol concentrations, than persons without depression, explained in part by varying glucocorticoid sensitivity.

    “individuals with major depressive disorder show flatter diurnal cortisol slopes (ie, higher overall cortisol concentrations) than in persons without depression, which is explained in part by varying levels of levels of glucocorticoid sensitivity or insensitivity”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pace et al, 2007 source

      Not checked in the free run.

    • cites Jarcho et al, 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sleep-immune interactions are bidirectional: immune activation alters sleep, and disrupted sleep impacts immune function.

    “data on sleep-immune interactions now demonstrate that these interactions are bidirectional: immune activation alters sleep, and disrupted sleep impacts immune function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IL1 receptors on endothelial cells, when activated by circulating IL1, induce local prostaglandin E2 production, which triggers additional brain responses to immune activation.

    “IL1 receptors are present on endothelial cells, which when activated by circulating IL1 induce local prostaglandin E2 production (Quan et al, 1998), an inflammatory signal that triggers additional brain responses to immune activation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Quan et al, 1998

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood-brain barrier active transport mechanisms are influenced by sleep and circadian processes and by sleep disruption.

    “BBB active transport mechanisms are influenced by sleep and circadian processes (Pan and Kastin, 2016) and by sleep disruption (He et al, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pan and Kastin, 2016

      Not checked in the free run.

    • cites He et al, 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Neural communication from the peripheral immune system to the CNS is a critical component of responses to systemic infection because it is quicker than other pathways and serves as an early warning system.

    “Neural communication from the peripheral immune system to the CNS is a critical component of responses to systemic infection because it is much quicker than the other forms of CNS-immune communication pathways and comprises the brain's early warning system for immune activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Blood-brain barrier transport of TNF increases during sepsis in young mice, but not in aged mice.

    “BBB transport of TNF increases during sepsis in young mice, but not in aged (Opp and Krueger, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Opp and Krueger, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytokines have an independent role in the regulation of sleep, and substantial evidence demonstrates that IL-1 and TNF are involved in physiological sleep regulation and in sleep changes during inflammatory diseases and pathologies.

    “Cytokines have an independent role in the regulation of sleep, and substantial evidence demonstrates that IL-1 and TNF are involved in physiological sleep regulation and in the changes in sleep that occur during inflammatory diseases and pathologies”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Obal and Krueger, 2003

      Not checked in the free run.

    • cites Krueger, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of IL-1 on sleep depend upon dose and the time of day it is given.

    “The effects of IL-1 on sleep depend upon dose and the time of day it is given (Opp et al, 1991)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Opp et al, 1991

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages appear to be the critical immune cell type driving increased NREM sleep, whereas NK cells, neutrophils, and T lymphocytes do not play a significant role.

    “Macrophages appear to be the critical immune cell type driving increased NREM sleep, whereas NK cells, neutrophils, and T lymphocytes do not play a significant role (Toth and Hughes, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Toth and Hughes, 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rabbits, intravenous injections of influenza virus are associated with large increases in NREM sleep and suppressed REM sleep, even though the virus does not replicate in this species.

    “In rabbits, intravenous injections of influenza virus are also associated with large increase in NREM sleep and suppressed REM sleep, even though the virus does not replicate in this species (Toth, 1995).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Toth, 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Healthy human volunteers injected with LPS manifest sleep changes, fever, cytokine expression, and hormonal changes somewhat similar to those seen in animals.

    “Healthy human volunteers injected with LPS manifest sleep changes, fever, cytokine expression, and hormonal changes (Mullington and Korth et al, 2000) somewhat similar to those seen in animals.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mullington and Korth et al, 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During the acute phase of CLP sepsis, NREM and REM sleep of rats increases during the dark period and is reduced during the light period.

    “During this period, NREM and REM sleep of rats increases during the dark period, whereas these sleep phases are reduced during the light period.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baracchi et al, 2011

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sepsis alters brain function, in agreement with observations that patients surviving sepsis often suffer severe and debilitating cognitive impairment.

    “These observations suggest that sepsis alters brain function, and are in agreement with observations that patients surviving sepsis often suffer severe and debilitating cognitive impairment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    NREM sleep increases after sleep deprivation, excessive food intake, or acute mild increases in ambient temperature.

    “NREM sleep increases after sleep deprivation, excessive food intake or acute mild increases in ambient temperature.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mice deficient in the 55 and 75 kD TNF receptors manifest reduced EEG delta power after viral challenge, whereas wild-type control mice show increased delta power.

    “mice deficient in the 55 and 75 kD TNF receptors manifest reduced EEG delta power, whereas in wild-type control mice, delta power increases (Kapas et al, 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kapas et al, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rabbits inoculated with Staphylococcus aureus show NREM sleep twice control within hours; this initial increase is followed by prolonged decreased NREM sleep, with REM sleep inhibited and animals febrile.

    “Within a few hours of S. aureus administration, NREM sleep is twice the amount as during comparable periods after control inoculation.This initial phase of increased duration and intensity of NREM sleep is followed by a more prolonged phase of decreased NREM sleep (Toth and Krueger, 1988).During both phases of the NREM sleep changes, REM sleep was inhibited and animals were febrile.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Toth and Krueger, 1988

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    After sleep deprivation, circulating IL-1 increases, brain levels of IL-1 mRNA increase, and the NREM sleep rebound is greatly attenuated if either IL-1 or TNF is blocked using antibodies or soluble receptors.

    “After sleep deprivation, circulating IL-1 increases, brain levels of IL-1 mRNA increase, and the NREM sleep rebound that would normally occur after sleep deprivation is greatly attenuated if either IL-1 or TNF is blocked using antibodies or soluble receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LPS is involved in sleep responses to gram-negative bacteria and has been studied in animal models and human volunteers.

    “Another bacterial product that is involved in sleep responses to gram-negative bacteria is the LPS component of cell wall endotoxin.LPS and has been intensively studied in animal models and humans volunteers with respect to effects on sleep”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mullington et al, 2000 source

      Not checked in the free run.

    • cites Krueger, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interferons have a major role in viral symptoms because influenza-infected IFN-receptor KO mice are less ill later in infection and recover sooner.

    “Interferons have a major role in viral symptoms because influenza-infected IFN-receptor KO mice are less ill later in the infection and recover sooner (Traynor et al, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Traynor et al, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL1 signaling in brain requires a brain-specific receptor accessory protein; mice lacking this protein have higher morbidity and mortality and sleep less during infection than wild-type mice.

    “IL1 signaling in brain requires a brain-specific receptor accessory protein (Dinarello, 2009); mice lacking this accessory protein have higher morbidity and mortality, and they sleep less during the infection, than do wild-type mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dinarello, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The IL1-receptor antagonist and TNF soluble receptor are normal gene products found in blood and brain, and their concentrations are altered by sleep.

    “The IL1-receptor antagonist and TNF soluble receptor are normal gene products found in blood and brain, and their concentrations are altered by sleep (Krueger, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Krueger, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNF protein has a sleep-associated diurnal rhythm in several brain areas, and IL-1 in cerebrospinal fluid varies with the sleep-wake cycle.

    “TNF protein also has a sleep-associated diurnal rhythm in several brain areas and IL-1in cerebrospinal fluid varies with the sleep-wake cycle (Lue et al, 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lue et al, 1988

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The impact of LPS on the human EEG differs from rabbits or rats, and humans require a higher LPS dose to increase NREM sleep than to suppress REM sleep.

    “However, the impact of LPS on the human EEG differs from those observed in rabbits or rats, and in humans it requires a higher LPS dose to increase NREM sleep than it does to suppress REM sleep.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Behavioral state scoring was performed blind to treatment group.

    “Behavioral state scoring was performed blind to treatment group, on each 10 s EEG epoch using synchronous video, EMG and EEG trace signatures to generate individual hypnograms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the cited translational study, anakinra reduced IL1 production by monocytes, showing peripheral effectiveness.

    “In this translational study, anakinra reduced IL1 production by monocytes, indicating it was effective in the periphery.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schmidt et al, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In contrast to preclinical animal studies, anakinra did not change sleep or memory function, although EEG slow-wave activity during SWS increased.

    “However, in contrast to preclinical animal studies, anakinra did not alter sleep or memory function, although EEG slow-wave activity during SWS actually increased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schmidt et al, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNF antagonism reduces daytime sleepiness in patients with sleep apnea and possibly improves other depressive symptoms among those with high levels of inflammation.

    “TNF antagonism has been found to reduce daytime sleepiness in patients with sleep apnea (Vgontzas et al, 2004), and it possibly improves other depressive symptoms among those with high levels of inflammation (Raison et al, 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Vgontzas et al, 2004

      Not checked in the free run.

    • cites Raison et al, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of NF-κB promotes IL-2, IL-6, IL-8, IL-15, and IL-18 production, each of which promotes sleep in rats.

    “Activation of NF-κB also promotes IL-2, IL-6, IL-8, IL-15, and IL-18 production, each of which promotes sleep in rats (Obal and Krueger, 2003;Krueger, 2008)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Obal and Krueger, 2003

      Not checked in the free run.

    • cites Krueger, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNF promotes sleep if microinjected into the anterior hypothalamus, whereas injection of a soluble TNF receptor into this area reduces sleep.

    “TNF promotes sleep if microinjected into the anterior hypothalamus, whereas injection of a soluble TNF receptor into this area reduces sleep (Kubota et al, 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kubota et al, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blockade of TNF induces short-term normalization of REM sleep in alcohol-dependent patients with high levels of REM sleep, and the decrease in REM sleep correlated with pharmacologic neutralization of biologically active TNF.

    “blockade of TNF has been found to induce a short-term normalization of REM sleep in alcohol-dependent patients with high levels of REM sleep (Irwin et al, 2009); the decrease in REM sleep correlated with pharmacologic neutralization of biologically active TNF.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Irwin et al, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1 inhibits discharge rates of serotonergic and cholinergic neurons in brainstem.

    “IL-1 inhibits discharge rates of serotonergic (Manfridi et al, 2003;Brambilla et al, 2007) and cholinergic (Brambilla et al, 2010) neurons in brainstem.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Manfridi et al, 2003

      Not checked in the free run.

    • cites Brambilla et al, 2007

      Not checked in the free run.

    • cites Brambilla et al, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within the hypothalamus, IL-1 increases c-Fos and inhibits wake-active neurons.

    “Within the hypothalamus, IL-1 increases c-Fos (Baker et al, 2005) and inhibits wake-active neurons (Alam et al, 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Baker et al, 2005

      Not checked in the free run.

    • cites Alam et al, 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NF-κB promotes IL-1 and TNF production and thus forms a positive feedback loop.

    “NF-κB promotes IL-1 and TNF production and thus forms a positive feedback loop.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Krueger, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infliximab treatment reduced spontaneous arousals during the night and increased sleep efficiency, and these sleep changes correlated with reduction in soluble TNF receptor 1.

    “Infliximab treatment reduced spontaneous arousals during the night and increased sleep efficiency, changes in sleep that correlated with reduction in the soluble TNF receptor 1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weinberger et al, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CBT-I is intensive and requires administration by highly trained therapists.

    “However, its implementation in community and primary care settings remains limited because CBT-I is intensive and requires administration by highly trained therapists; (Morin, 2015)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morin, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNF blockade improved sleep continuity and increased sleep depth in patients with RA.

    “Zamarron et al (2004)also found that TNF blockade improved sleep continuity and increased sleep depth in patients with RA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zamarron et al, 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1 increases serotonergic activity in brain regions implicated in sleep regulation, and an intact serotonergic system is required for the full effects of IL-1 on sleep to manifest.

    “IL-1 increases serotonergic activity in brain regions implicated in sleep regulation (Gemma et al, 1997), and an intact serotonergic system is required for the full effects of IL-1 on sleep to manifest (Imeri et al, 1997(Imeri et al, , 1999)).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gemma et al, 1997

      Not checked in the free run.

    • cites Imeri et al, 1997

      Not checked in the free run.

    • cites Imeri et al, 1999

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    In the Miller et al study, subjects were randomized into a treatment arm using infliximab or placebo.

    “Subjects then were randomized into a treatment arm, using the TNF antagonist infliximab, or placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weinberger et al, 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The TCC-induced reduction in cellular inflammation is independent of improvements in sleep and occurs through other effector mechanisms such as sympovagal balance.

    “suggesting that these changes are independent of improvements in sleep but rather through changes in other effector mechanisms such as the sympovagal balance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In insomnia patients, CBT-I and Tai chi can effectively reverse activation of inflammatory pathways associated with insomnia.

    “In insomnia patients, CBT-I and the mind-body intervention, Tai chi, can effectively reverse that activation of inflammatory pathways associated with insomnia (Irwin et al, 2014(Irwin et al, , 2015)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Irwin et al, 2014

      Not checked in the free run.

    • cites Irwin et al, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Treatment of sleep disturbance may represent a third pillar, along with diet and physical activity, for lifestyle changes with health benefits.

    “Finally, treatment of sleep disturbance may represent a third pillar, along with diet and physical activity, to promote lifestyle changes with benefits on health.”
    Quote in the paperNot a substantial claim
109 of 109

  • The paper relies on this without support.

    Findings from animal models about inflammatory cytokines regulating sleep can be generalized to humans.

    “substantial evidence from translational animal models has revealed that inflammatory cytokines homeostatically regulate sleep.”
    “the chronic disruption of circadian rhythm magnifies inflammatory responses to challenge with endotoxin in an animal model of shift work or chronic jet lag (Castanon-Cervantes et al, 2010)”

  • The paper relies on this without support.

    Circulating inflammatory markers such as CRP, IL-6, and TNF reflect innate immune activity relevant to inflammatory disease risk.

    “markers of CRP, IL-6, and TNF in healthy adults”
    “systemic markers of inflammation”

  • The paper relies on this without support.

    Monocytes are a primary source of inflammatory cytokines in peripheral blood.

    “Given that monocytes are a primary source for inflammatory cytokines in the peripheral blood”

  • The paper relies on this without support.

    IL-6 induces CRP.

    “It is known that IL-6 induces CRP”

  • The paper relies on this without support.

    Elevated inflammation contributes to biological aging.

    “Such elevated levels of inflammation are thought to contribute to biological aging.”

  • The paper relies on this without support.

    Findings from animal models of infection and sleep can be generalized to human sleep-immune regulation.

    “As a preclinical model, influenza infection of mice is clinically relevant because mouse-adapted strains of this virus can be introduced into the respiratory tract and can fully replicate in the lungs, causing a severe acute phase response.”

  • The paper relies on this without support.

    Measures of sleep architecture in animal models, such as NREM/REM and EEG power, correspond to human sleep states and can inform human sleep-immune conclusions.

    “Sleep microstructure also showed significant alteration in the LPS mice specifically during the dark cycle, caused by significantly longer average NREM cycle durations.”

  • The paper relies on this without support.

    Numerous clinical studies targeting inflammatory processes in pathology show improvement in sleep disturbances associated with disease.

    “Whereas numerous clinical studies targeting inflammatory processes within the context of pathology demonstrate improvement in sleep disturbances associated with disease”

  • The paper relies on this without support.

    There is an absence of empirical randomized controlled trial data examining the effects of pharmacologic treatment of insomnia on inflammatory or other immune outcomes.

    “Unfortunately, there is an absence of empirical randomized controlled trial data, which have examined the effects of pharmacologic treatment of insomnia on inflammatory or other immune outcomes.”

  • The paper relies on this without support.

    Pharmacological treatment that improves insomnia might have confounding influences on measures of inflammation.

    “In contrast, pharmacological treatment that improves insomnia might have confounding influences on measures of inflammation.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Elevated melatonin concentrations may not be the only mechanism by which tart cherry juice improves sleep, as sleep regulation is also influenced by proinflammatory cytokines.

    “It must be noted that elevated melatonin concentrations may not be only mechanism at work as sleep regulation is also influenced by proinflammatory cytokines [3].”

    From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [3]

  • Complete deprivation of nocturnal sleep reduces growth by one and a half.

    “growth is reduced by one and a half by complete deprivation of nocturnal sleep [86].”

    From Probiotics Regulate Gut Microbiota: An Effective Method to Improve Immunity (2021) · cites this paper as [86]

  • Poor sleep quality that interferes with the normal circadian rhythm promotes an increase in IL-6 during sleep.

    “when poor sleep quality interferes with the normal circadian rhythm, the increase in IL-6 during sleep is promoted”

    From Probiotics Regulate Gut Microbiota: An Effective Method to Improve Immunity (2021) · cites this paper as [86]

  • Sleep regulates inflammatory processes.

    “Sleep has been shown to regulate inflammatory processes.”

    From Probiotics Regulate Gut Microbiota: An Effective Method to Improve Immunity (2021) · cites this paper as [86]

  • During slow-wave sleep, production and release of cytokines such as interleukin-1 and tumor necrosis factor increase.

    “During slow-wave sleep (SWS) the production and release of cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), increase.”

    From Prodromal dreams (2025) · cites this paper as [31]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Sleep efficiency is defined as time awake but used as a measure of time asleep

    Minor

    The paper defines sleep efficiency as the percentage of the sleep period spent awake. It later describes decreased awake time after sleep onset alongside increased sleep efficiency, treating efficiency as moving in the opposite direction from awake time.

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5 of the 259 references couldn’t be matched to a known paper.

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Related

Authors
Irwin, M. R., & Opp, M. R.
Affiliations
  • University of California, Los Angeles (US)
  • University of Washington (US)
Corresponding author
Irwin, Michael R
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2016-08-11
Volume
42
Issue
1
Pages
129-155
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2016.148
PMC
PMC5143488
OpenAlex
W2507645382
Semantic Scholar
65ba331642fa998a4c555d3723e532bc541e5962
Cited by
624
References
259
Citations by year
2026: 97 · 2025: 114 · 2024: 83 · 2023: 74 · 2022: 75 · 2021: 69 · 2020: 47 · 2019: 30 · 2018: 23 · 2017: 7 · 2016: 4 · 2013: 1
FWCI
2.28
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG026364, R01AG034588)
  • National Heart, Lung, and Blood Institute (R01HL079955, R01HL095799)
  • National Cancer Institute (R01CA160245, R01CA119159)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords
sleep, innate immunity, insomnia, sleep deprivation, sleep duration, inflammation, inflammaging, cellular aging, major depressive disorder, inflammatory mediators, sleep homeostasis, sleep macrostructure, insomnia treatment
MeSH terms
Animals, Humans, Immunity, Innate, Inflammation, Sleep, Sleep Wake Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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