The discovery of reciprocal connections between the central nervous system, sleep and the immune system has shown that sleep enhances immune defences and that afferent signals from immune cells promote sleep. One mechanism by which sleep is proposed to provide a survival advantage is in terms of supporting a neurally integrated immune system that might anticipate injury and infectious threats. However, in modern times, chronic social threats can drive the development of sleep disturbances in humans, which can contribute to the dysregulation of inflammatory and antiviral responses. In this Review, I describe our current understanding of the relationship between sleep dynamics and host defence mechanisms, with a focus on cytokine responses, the neuroendocrine and autonomic pathways that connect sleep with the immune system and the role of inflammatory peptides in the homeostatic regulation of sleep. Furthermore, I discuss the therapeutic potential of harnessing these reciprocal mechanisms of sleep–immune regulation to mitigate the risk of inflammatory and infectious diseases.
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Ohayon, M. M. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med. Rev. 6, 97–111 (2002).
Irwin, M. R. Why sleep is important for health: a psychoneuroimmunology perspective. Annu. Rev. Psychol. 66, 143–172 (2015).
Harris, H. Role of chemotaxis in inflammation. Physiol. Rev. 34, 529–562 (1954).
Ishimori, K. True cause of sleep: a hypnogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igakkai Zasshi 23, 429–459 (1909).
Imeri, L. & Opp, M. R. How (and why) the immune system makes us sleep. Nat. Rev. Neurosci. 10, 199–210 (2009). This seminal review details the pathways of immune signalling to the brain and how cytokines interact with neurochemical systems to regulate the immune system to promote survival from infection.
Krueger, J. M., Pappenheimer, J. R. & Karnovsky, M. L. Sleep-promoting factor S: purification and properties. Proc. Natl Acad. Sci. USA 75, 5235–5238 (1978).
Krueger, J. M., Walter, J., Dinarello, C. A., Wolff, S. M. & Chedid, L. Sleep-promoting effects of endogenous pyrogen (interleukin-1). Am. J. Physiol. 246, R994–999 (1984).
Krueger, J. M., Frank, M. G., Wisor, J. P. & Roy, S. Sleep function: toward elucidating an enigma. Sleep Med. Rev. 28, 46–54 (2016).
McEwen, B. S. Sleep deprivation as a neurobiologic and physiologic stressor: allostasis and allostatic load. Metabolism 55, S20–23 (2006).
Irwin, M. R. & Cole, S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625–632 (2011).
Westermann, J., Lange, T., Textor, J. & Born, J. System consolidation during sleep - a common principle underlying psychological and immunological memory formation. Trends Neurosci. 38, 585–597 (2015). This theoretical treatise proposes that sleep benefits the consolidation of psychological memory and likewise supports immunological memory formation, which is conveyed by the same sleep-associated processes.
Irwin, M. R. & Opp, M. R. Sleep health: reciprocal regulation of sleep and innate immunity. Neuropsychopharmacology 42, 129–155 (2017).
Lange, T., Dimitrov, S. & Born, J. Effects of sleep and circadian rhythm on the human immune system. Ann. N.Y. Acad. Sci. 1193, 48–59 (2010).
Vgontzas, A. N. et al. Circadian interleukin-6 secretion and quantity and depth of sleep. J. Clin. Endocrinol. Metab. 84, 2603–2607 (1999).
Dimitrov, S., Besedovsky, L., Born, J. & Lange, T. Differential acute effects of sleep on spontaneous and stimulated production of tumor necrosis factor in men. Brain Behav. Immun. 47, 201–210 (2015).
Redwine, L., Hauger, R., Gillin, J. & Irwin, M. Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J. Clin. Endocrinol. Metab. 85, 3597–3603 (2000).
Redwine, L., Dang, J., Hall, M. & Irwin, M. Disordered sleep, nocturnal cytokines, and immunity in alcoholics. Psychosom. Med. 65, 75–85 (2003).
Dimitrov, S. et al. Sleep enhances IL-6 trans-signaling in humans. FASEB J. 20, 2174–2176 (2006).
Vgontzas, A. N. et al. Rapid eye movement sleep correlates with the overall activities of the hypothalamic-pituitary-adrenal axis and sympathetic system in healthy humans. J. Clin. Endocrinol. Metab. 82, 3278–3280 (1997).
Somers, V. K., Dyken, M. E., Mark, A. L. & Abboud, F. M. Sympathetic-nerve activity during sleep in normal subjects. N. Engl. J. Med. 328, 303–307 (1993).
Hornyak, M., Cejnar, M., Elam, M., Matousek, M. & Wallin, B. G. Sympathetic muscle nerve activity during sleep in man. Brain 114, 1281–1295 (1991).
Okada, H., Iwase, S., Mano, T., Sugiyama, Y. & Watanabe, T. Changes in muscle sympathetic nerve activity during sleep in humans. Neurology 41, 1961–1966 (1991).
Trinder, J. et al. Autonomic activity during human sleep as a function of time and sleep stage. J. Sleep Res. 10, 253–264 (2001).
Palma, J. A. et al. Increased sympathetic and decreased parasympathetic cardiac tone in patients with sleep related alveolar hypoventilation. Sleep 36, 933–940 (2013).
Irwin, M., Thompson, J., Miller, C., Gillin, J. & Ziegler, M. Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications. J. Clin. Endocrinol. Metab. 84, 1979–1985 (1999).
Dodt, C., Breckling, U., Derad, I., Fehm, H. L. & Born, J. Plasma epinephrine and norepinephrine concentrations of healthy humans associated with nighttime sleep and morning arousal. Hypertension 30, 71–76 (1997).
Rasch, B., Dodt, C., Molle, M. & Born, J. Sleep-stage-specific regulation of plasma catecholamine concentration. Psychoneuroendocrinology 32, 884–891 (2007).
Davis, K. C. & Raizen, D. M. A mechanism for sickness sleep: lessons from invertebrates. J. Physiol. 595, 5415–5424 (2017).
Hill, A. J., Mansfield, R., Lopez, J. M., Raizen, D. M. & Van Buskirk, C. Cellular stress induces a protective sleep-like state in C. elegans. Curr. Biol. 24, 2399–2405 (2014).
Lenz, O., Xiong, J., Nelson, M. D., Raizen, D. M. & Williams, J. A. FMRFamide signaling promotes stress-induced sleep in Drosophila. Brain Behav. Immun. 47, 141–148 (2015).
Slavich, G. M. & Irwin, M. R. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol. Bull. 140, 774–815 (2014). This review proposes the social signal transduction hypothesis of depression and provides one of the most detailed descriptions of the relationships between stress-induced activation of inflammatory responses and sensitivity to psychosocial stressors, which can lead to depression.
Irwin, M. R., Olmstead, R. & Carroll, J. E. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol. Psychiatry 80, 40–52 (2016). This systematic review provides the first comprehensive assessment of the global evidence linking sleep disturbance, sleep duration and inflammation in adult humans and shows that sleep disturbance and long sleep duration should be regarded as behavioural risk factors for inflammation.
Wright, K. P. Jr. et al. Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav. Immun. 47, 24–34 (2015).
Irwin, M. R., Witarama, T., Caudill, M., Olmstead, R. & Breen, E. C. Sleep loss activates cellular inflammation and signal transducer and activator of transcription (STAT) family proteins in humans. Brain Behav. Immun. 47, 86–92 (2015).
Irwin, M. R., Carrillo, C. & Olmstead, R. Sleep loss activates cellular markers of inflammation: sex differences. Brain Behav. Immun. 24, 54–57 (2010).
Carroll, J. E. et al. Sleep deprivation and divergent toll-like receptor-4 activation of cellular inflammation in aging. Sleep 38, 205–211 (2015).
Irwin, M. R., Wang, M., Campomayor, C. O., Collado-Hidalgo, A. & Cole, S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch. Intern. Med. 166, 1756–1762 (2006). This experimental study is the first to show that sleep deprivation induces an activation of cellular inflammation and inflammatory transcriptional profiles, owing to increased signalling through the NF-κB and AP-1 inflammatory signalling pathways.
Irwin, M. R. et al. Sleep loss activates cellular inflammatory signaling. Biol. Psychiatry 64, 538–540 (2008).
Krueger, J. M. The role of cytokines in sleep regulation. Curr. Pharm. Des. 14, 3408–3416 (2008).
Couzin-Frankel, J. Inflammation bares a dark side. Science 330, 1621 (2010).
Park, H. et al. Sleep and inflammation during adolescence. Psychosom. Med. 78, 677–685 (2016).
Youngstedt, S. D. & Kripke, D. F. Long sleep and mortality: rationale for sleep restriction. Sleep Med. Rev. 8, 159–174 (2004).
O’Connor, M. F. et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav. Immun. 23, 887–897 (2009).
Cho, H. J., Seeman, T. E., Kiefe, C. I., Lauderdale, D. S. & Irwin, M. R. Sleep disturbance and longitudinal risk of inflammation: moderating influences of social integration and social isolation in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Brain Behav. Immun. 46, 319–326 (2015).
Smagula, S. F., Stone, K. L., Fabio, A. & Cauley, J. A. Risk factors for sleep disturbances in older adults: evidence from prospective studies. Sleep Med. Rev. 25, 21–30 (2016).
O’Connor, M. F. & Irwin, M. R. Links between behavioral factors and inflammation. Clin. Pharmacol. Ther. 87, 479–482 (2010).
Irwin, M. R. et al. Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: a randomized controlled trial. Biol. Psychiatry 78, 721–729 (2015). This report describes the results of the first randomized controlled trial to treat insomnia and reverse transcriptional, cellular and systemic profiles of inflammation over a long-term, one-year follow-up in older adults.
Irwin, M. et al. Tai Chi, cellular inflammation, and transcriptome dynamics in breast cancer survivors with insomnia: a randomized controlled trial. J. Natl Cancer Inst. 50, 295–301 (2014).
Neale, E. P., Batterham, M. J. & Tapsell, L. C. Consumption of a healthy dietary pattern results in significant reductions in C-reactive protein levels in adults: a meta-analysis. Nutr. Res. 36, 391–401 (2016).
Hayashino, Y. et al. Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Metabolism 63, 431–440 (2014).
Born, J., Lange, T., Hansen, K., Molle, M. & Fehm, H. L. Effects of sleep and circadian rhythm on human circulating immune cells. J. Immunol. 158, 4454–4464 (1997).
Lange, T., Dimitrov, S., Fehm, H. L., Westermann, J. & Born, J. Shift of monocyte function toward cellular immunity during sleep. Arch. Intern. Med. 166, 1695–1700 (2006). Born et al. and Lange et al. are among the first to have experimentally examined the role of nocturnal sleep and its relation to circadian rhythm in the regulation of the immune system and to show that sleep supports ongoing immune defences in extravascular lymphoid tissue during a time of diminished acute antigenic challenge.
Besedovsky, L., Lange, T. & Haack, M. The sleep-immune crosstalk in health and disease. Physiol. Rev. 99, 1325–1380 (2019).
Dimitrov, S., Lange, T., Tieken, S., Fehm, H. L. & Born, J. Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans. Brain Behav. Immun. 18, 341–348 (2004).
Lange, T., Dimitrov, S., Fehm, H. L. & Born, J. Sleep-like concentrations of growth hormone and cortisol modulate type1 and type2 in-vitro cytokine production in human T cells. Int. Immunopharmacol. 6, 216–225 (2006).
Burns, V. E., Drayson, M., Ring, C. & Carroll, D. Perceived stress and psychological well-being are associated with antibody status after meningitis C conjugate vaccination. Psychosom. Med. 64, 963–970 (2002).
Pressman, S. D. et al. Loneliness, social network size, and immune response to influenza vaccination in college freshmen. Health Psychol. 24, 297–306 (2005).
Dopp, J. M., Reichmuth, K. J. & Morgan, B. J. Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management. Curr. Hypertens. Rep. 9, 529–534 (2007).
Prather, A. A. et al. Sleep and antibody response to hepatitis B vaccination. Sleep 35, 1063–1069 (2012).
Taylor, D. J., Kelly, K., Kohut, M. L. & Song, K. S. Is insomnia a risk factor for decreased influenza vaccine response? Behav. Sleep Med. 15, 270–287 (2017).
Lange, T., Dimitrov, S., Bollinger, T., Diekelmann, S. & Born, J. Sleep after vaccination boosts immunological memory. J. Immunol. 187, 283–290 (2011). This experimental study looks at the role of sleep in promoting antigen-specific T cell-mediated immunity to a vaccination and also provides novel evidence that slow wave sleep activity immediately after vaccination drives T H 1 cell-mediated immune responses that persist over the following year.
Lange, T., Perras, B., Fehm, H. L. & Born, J. Sleep enhances the human antibody response to hepatitis A vaccination. Psychosom. Med. 65, 831–835 (2003).
Spiegel, K., Sheridan, J. F. & Van Cauter, E. Effect of sleep deprivation on response to immunization. JAMA 288, 1471–1472 (2002).
Benedict, C., Brytting, M., Markstrom, A., Broman, J. E. & Schioth, H. B. Acute sleep deprivation has no lasting effects on the human antibody titer response following a novel influenza A H1N1 virus vaccination. BMC Immunol. 13, 1 (2012).
Miller, G. E. et al. Psychological stress and antibody response to influenza vaccination: when is the critical period for stress, and how does it get inside the body? Psychosom. Med. 66, 215–223 (2004).
Patel, S. R. et al. A prospective study of sleep duration and pneumonia risk in women. Sleep 35, 97–101 (2012).
Cohen, S., Doyle, W. J., Alper, C. M., Janicki-Deverts, D. & Turner, R. B. Sleep habits and susceptibility to the common cold. Arch. Intern. Med. 169, 62–67 (2009).
Prather, A. A., Janicki-Deverts, D., Hall, M. H. & Cohen, S. Behaviorally assessed sleep and susceptibility to the common cold. Sleep 38, 1353–1359 (2015). This study is the first to show that objective measures of short sleep duration are associated with increased susceptibility to the common cold after experimental viral exposure.
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).
Irwin, M. R. et al. Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications. Clin. Infect. Dis. 56, 1085–1093 (2013).
Toth, L. A. Sleep, sleep deprivation and infectious disease: studies in animals. Adv. Neuroimmunol. 5, 79–92 (1995).
Kuo, T. H. & Williams, J. A. Increased sleep promotes survival during a bacterial infection in Drosophila. Sleep 37, 1077–1086 (2014).
Kim, J. Y. et al. Melatonin improves inflammatory cytokine profiles in lung inflammation associated with sleep deprivation. Mol. Med. Rep. 5, 1281–1284 (2012).
Dimitrov, S., Lange, T., Fehm, H. L. & Born, J. A regulatory role of prolactin, growth hormone, and corticosteroids for human T cell production of cytokines. Brain Behav. Immun. 18, 368–374 (2004).
Abell, J. G., Shipley, M. J., Ferrie, J. E., Kivimaki, M. & Kumari, M. Recurrent short sleep, chronic insomnia symptoms and salivary cortisol: a 10-year follow-up in the Whitehall II study. Psychoneuroendocrinology 68, 91–99 (2016).
Castro-Diehl, C. et al. Association of sleep duration and quality with alterations in the hypothalamic-pituitary adrenocortical axis: the Multi-Ethnic Study of Atherosclerosis (MESA). J. Clin. Endocrinol. Metab. 100, 3149–3158 (2015).
Webster, J. C., Oakley, R. H., Jewell, C. M. & Cidlowski, J. A. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc. Natl Acad. Sci. USA 98, 6865–6870 (2001).
Li, L. B., Goleva, E., Hall, C. F., Ou, L. S. & Leung, D. Y. Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J. Allergy Clin. Immunol. 114, 1059–1069 (2004).
Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016). This theoretical Review builds upon the ‘pathogen host defence’ hypothesis of depression and the evolutionary advantage provided by crosstalk between the immune system and the brain, and it informs the current understanding of the pathways of communication between the innate and adaptive immune systems in the regulation of neurotransmitters and neurocircuits relevant to depression.
Floam, S. et al. Sleep characteristics as predictor variables of stress systems markers in insomnia disorder. J. Sleep Res. 24, 296–304 (2015).
Paugh, S. W., Bonten, E. J. & Evans, W. E. Inflammasome-mediated glucocorticoid resistance: the receptor rheostat. Mol. Cell. Oncol. 3, e1065947 (2016).
Walsh, C. P., Lim, A., Marsland, A. L., Ferrell, R. E. & Manuck, S. B. Circulating Interleukin-6 concentration covaries inversely with self-reported sleep duration as a function of polymorphic variation in the glucocorticoid receptor. Brain Behav. Immun. 78, 21–30 (2019).
Boudreau, P., Yeh, W. H., Dumont, G. A. & Boivin, D. B. Circadian variation of heart rate variability across sleep stages. Sleep 36, 1919–1928 (2013).
Irwin, M. R. & Ziegler, M. Sleep deprivation potentiates activation of cardiovascular and catecholamine responses in abstinent alcoholics. Hypertension 45, 252–257 (2005).
Tobaldini, E. et al. One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians. Eur. J. Intern. Med. 24, 664–670 (2013).
Vgontzas, A. N., Fernandez-Mendoza, J., Liao, D. & Bixler, E. O. Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep Med. Rev. 17, 241–254 (2013).
Bell, K. A., Kobayashi, I., Chen, Y. & Mellman, T. A. Nocturnal autonomic nervous system activity and morning proinflammatory cytokines in young adult African Americans. J. Sleep Res. 26, 510–515 (2017).
De Lorenzo, B. H., de Oliveira Marchioro, L., Greco, C. R. & Suchecki, D. Sleep-deprivation reduces NK cell number and function mediated by beta-adrenergic signalling. Psychoneuroendocrinology 57, 134–143 (2015).
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).
Fang, J., Sanborn, C. K., Renegar, K. B., Majde, J. A. & Krueger, J. M. Influenza viral infections enhance sleep in mice. Proc. Soc. Exp. Biol. Med. 210, 242–252 (1995).
Drake, C. L. et al. Effects of an experimentally induced rhinovirus cold on sleep, performance, and daytime alertness. Physiol. Behav. 71, 75–81 (2000).
Kapas, L. et al. Spontaneous and influenza virus-induced sleep are altered in TNF-alpha double-receptor deficient mice. J. Appl. Physiol. 105, 1187–1198 (2008).
Davis, C. J. et al. The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice. Brain Behav. Immun. 47, 35–43 (2015).
Toth, L. A. & Krueger, J. M. Alteration of sleep in rabbits by Staphylococcus aureus infection. Infect. Immun. 56, 1785–1791 (1988).
Opp, M. R. & Toth, L. A. Neural-immune interactions in the regulation of sleep. Front. Biosci. 8, D768–D779 (2003).
Granger, J. I., Ratti, P. L., Datta, S. C., Raymond, R. M. & Opp, M. R. Sepsis-induced morbidity in mice: effects on body temperature, body weight, cage activity, social behavior and cytokines in brain. Psychoneuroendocrinology 38, 1047–1057 (2013).
Baracchi, F., Ingiosi, A. M., Raymond, R. M. Jr & Opp, M. R. Sepsis-induced alterations in sleep of rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1467–R1478 (2011).
Mullington, J. et al. Dose-dependent effects of endotoxin on human sleep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R947–955 (2000).
Castanon-Cervantes, O. et al. Dysregulation of inflammatory responses by chronic circadian disruption. J. Immunol. 185, 5796–5805 (2010).
Lange, T., Marshall, L., Spath-Schwalbe, E., Fehm, H. L. & Born, J. Systemic immune parameters and sleep after ultra-low dose administration of IL-2 in healthy men. Brain Behav. Immun. 16, 663–674 (2002).
Krueger, J. M. et al. Sleep as a fundamental property of neuronal assemblies. Nat. Rev. Neurosci. 9, 910–919 (2008).
Bjurstrom, M. F., Olmstead, R. & Irwin, M. R. Reciprocal relationship between sleep macrostructure and evening and morning cellular inflammation in rheumatoid arthritis. Psychosom. Med. 79, 24–33 (2017).
Lue, F. A. et al. Sleep and cerebrospinal fluid interleukin-1-like activity in the cat. Int. J. Neurosci. 42, 179–183 (1988).
Zamarron, F., Maceiras, F., Mera, A. & Gomez-Reino, J. J. Effects of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis. Ann. Rheum. Dis. 63, 88–90 (2004).
Irwin, M. R., Olmstead, R., Valladares, E. M., Breen, E. C. & Ehlers, C. L. Tumor necrosis factor antagonism normalizes rapid eye movement sleep in alcohol dependence. Biol. Psychiatry 66, 191–195 (2009).
Opp, M. R., Obal, F. Jr & Krueger, J. M. Interleukin 1 alters rat sleep: temporal and dose-related effects. Am. J. Physiol. 260, R52–R58 (1991).
Toth, L. A., Tolley, E. A., Broady, R., Blakely, B. & Krueger, J. M. Sleep during experimental trypanosomiasis in rabbits. Proc. Soc. Exp. Biol. Med. 205, 174–181 (1994).
Schmidt, E. M. et al. Effects of an interleukin-1 receptor antagonist on human sleep, sleep-associated memory consolidation, and blood monocytes. Brain Behav. Immun. 47, 178–185 (2015).
Toda, H., Williams, J. A., Gulledge, M. & Sehgal, A. A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila. Science 363, 509–515 (2019). This ground-breaking study identifies an antimicrobial peptide, nemuri, that is a bona fide sleep homeostasis factor that drives prolonged ‘sleep’, as defined by locomotor activity, and also promotes survival after infection.
Vanderheyden, W. M. et al. Astrocyte expression of the Drosophila TNF-alpha homologue, Eiger, regulates sleep in flies. PLOS Genet. 14, e1007724 (2018).
Lasry, A. & Ben-Neriah, Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 36, 217–228 (2015).
Carroll, J. E. et al. Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans. Brain Behav. Immun. 51, 223–229 (2016).
Prather, A. A., Hecht, F. M. & Epel, E. S. Factors related to telomere length. Brain Behav. Immun. 53, 279 (2016).
Cribbet, M. R. et al. Cellular aging and restorative processes: subjective sleep quality and duration moderate the association between age and telomere length in a sample of middle-aged and older adults. Sleep 37, 65–70 (2014).
Carroll, J. E. et al. Insomnia and telomere length in older adults. Sleep 39, 559–564 (2016).
Carroll, J. E. et al. Epigenetic aging and immune senescence in women with insomnia symptoms: findings from the Women’s Health Initiative Study. Biol. Psychiatry 81, 136–144 (2017).
Ligthart, S. et al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biol. 17, 255 (2016).
Chen, B. H. et al. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY) 8, 1844–1865 (2016).
Lo, J. C., Groeger, J. A., Cheng, G. H., Dijk, D. J. & Chee, M. W. Self-reported sleep duration and cognitive performance in older adults: a systematic review and meta-analysis. Sleep Med. 17, 87–98 (2016).
Shi, L. et al. Sleep disturbances increase the risk of dementia: a systematic review and meta-analysis. Sleep Med. Rev. 40, 4–16 (2018).
Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).
Irwin, M. R. & Vitiello, M. V. Implications of sleep disturbance and inflammation for Alzheimer’s disease dementia. Lancet Neurol. 18, 296–306 (2019).
Cho, H. J. et al. Sleep disturbance and depression recurrence in community-dwelling older adults: a prospective study. Am. J. Psychiatry 165, 1543–1550 (2008).
Cho, H. J., Eisenberger, N. I., Olmstead, R., Breen, E. C. & Irwin, M. R. Preexisting mild sleep disturbance as a vulnerability factor for inflammation-induced depressed mood: a human experimental study. Transl Psychiatry 6, e750 (2016).
Irwin, M. R. et al. Tai Chi Chih compared with cognitive behavioral therapy for the treatment of insomnia in survivors of breast cancer: a randomized, partially blinded, noninferiority trial. J. Clin. Oncol. 35, 2656–2665 (2017).
Black, D. S., O’Reilly, G. A., Olmstead, R., Breen, E. C. & Irwin, M. R. Mindfulness meditation and improvement in sleep quality and daytime impairment among older adults with sleep disturbances: a randomized clinical trial. JAMA Intern. Med. 175, 494–501 (2015).
McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).
Smagula, S. F. et al. Actigraphy- and polysomnography-measured sleep disturbances, inflammation, and mortality among older men. Psychosom. Med. 78, 686–696 (2016).
Cole, S. W. et al. Computational identification of gene-social environment interaction at the human IL6 locus. Proc. Natl Acad. Sci. USA 107, 5681–5686 (2010).
Sanders, V. M. & Straub, R. H. Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav. Immun. 16, 290–332 (2002).
Flierl, M. A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725 (2007).
Flierl, M. A. et al. Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response. PLOS ONE 4, e4414 (2009).
Grebe, K. M. et al. Cutting edge: sympathetic nervous system increases proinflammatory cytokines and exacerbates influenza A virus pathogenesis. J. Immunol. 184, 540–544 (2009).
Levick, S. P., Murray, D. B., Janicki, J. S. & Brower, G. L. Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart. Hypertension 55, 270–276 (2010).
Straub, R. H., Bijlsma, J. W., Masi, A. & Cutolo, M. Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases—the 10-year update. Semin. Arthritis Rheum. 43, 392–404 (2013).
Livingston, G. et al. Dementia prevention, intervention, and care. Lancet 390, 2673–2734 (2017).
Prather, A. A., Epel, E. S., Cohen, B. E., Neylan, T. C. & Whooley, M. A. Gender differences in the prospective associations of self-reported sleep quality with biomarkers of systemic inflammation and coagulation: findings from the Heart and Soul Study. J. Psychiatr. Res. 47, 1228–1235 (2013).
Prather, A. A., Vogelzangs, N. & Penninx, B. W. Sleep duration, insomnia, and markers of systemic inflammation: results from the Netherlands Study of Depression and Anxiety (NESDA). J. Psychiatr. Res. 60, 95–102 (2015).
Bakour, C. et al. Sleep duration trajectories and systemic inflammation in young adults: results from the National Longitudinal Study of Adolescent to Adult Health (Add Health). Sleep 40, zsx156 (2017).
Grandner, M. A. et al. Extreme sleep durations and increased C-reactive protein: effects of sex and ethnoracial group. Sleep 36, 769–779 (2013).
Zielinski, M. R., Dunbrasky, D. L., Taishi, P., Souza, G. & Krueger, J. M. Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-alpha and lipopolysaccharide in mice. Sleep 36, 1227–1238 (2013).
Vitkovic, L., Bockaert, J. & Jacque, C. “Inflammatory” cytokines: neuromodulators in normal brain? J. Neurochem. 74, 457–471 (2000).
Banks, W. A. The blood-brain barrier in neuroimmunology: tales of separation and assimilation. Brain Behav. Immun. 44, 1–8 (2015).
Pan, W. & Kastin, A. J. The blood-brain barrier: regulatory roles in wakefulness and sleep. Neuroscientist 23, 124–136 (2017).
Opp, M. R. & Krueger, J. M. Sleep and immunity: a growing field with clinical impact. Brain Behav. Immun. 47, 1–3 (2015).
D’Mello, C., Le, T. & Swain, M. G. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J. Neurosci. 29, 2089–2102 (2009).
Shearer, W. T. et al. Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J. Allergy Clin. Immunol. 107, 165–170 (2001).
Meier-Ewert, H. K. et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J. Am. Coll. Cardiol. 43, 678–683 (2004).
Moldofsky, H., Lue, F. A., Davidson, J. R. & Gorczynski, R. Effects of sleep deprivation on human immune functions. FASEB J. 3, 1972–1977 (1989).
Vgontzas, A. N. et al. Daytime napping after a night of sleep loss decreases sleepiness, improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion. Am. J. Physiol. Endocrinol. Metab. 292, E253–E261 (2007).
Frey, D. J., Fleshner, M. & Wright, K. P. Jr. The effects of 40 hours of total sleep deprivation on inflammatory markers in healthy young adults. Brain Behav. Immun. 21, 1050–1057 (2007).
Sauvet, F. et al. Effect of acute sleep deprivation on vascular function in healthy subjects. J. Appl. Physiol. 108, 68–75 (2010).
Haack, M. et al. Diurnal variations of interleukin-6 plasma levels are confounded by blood drawing procedures. Psychoneuroendocrinology 27, 921–931 (2002).
Chennaoui, M. et al. Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men. Cytokine 56, 318–324 (2011).
Haack, M., Sanchez, E. & Mullington, J. M. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep 30, 1145–1152 (2007).
Vgontzas, A. N. et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J. Clin. Endocrinol. Metab. 89, 2119–2126 (2004).
Schmid, S. M. et al. Disturbed glucoregulatory response to food intake after moderate sleep restriction. Sleep 34, 371–377 (2011).
Irwin, M. et al. Nocturnal proinflammatory cytokine-associated sleep disturbances in abstinent African American alcoholics. Brain Behav. Immun. 18, 349–360 (2004).
Abedelmalek, S. et al. Effect of time of day and partial sleep deprivation on plasma concentrations of IL-6 during a short-term maximal performance. Eur. J. Appl. Physiol. 113, 241–248 (2013).
Faraut, B. et al. Benefits of napping and an extended duration of recovery sleep on alertness and immune cells after acute sleep restriction. Brain Behav. Immun. 25, 16–24 (2011).
Stamatakis, K. A. & Punjabi, N. M. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 137, 95–101 (2010).
van Leeuwen, W. M. et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLOS ONE 4, e4589 (2009).
The author acknowledges research support provided by the US National Institutes of Health (Grants R01AG051944, R01AG056424-01, R01AG026364, R01CA160245, R01AG057750 and R01CA207130).
The author declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Difficulty initiating or maintaining sleep, early awakening, interrupted or non-restorative sleep, and associated impairments in daytime functioning, which must be present for at least 3 nights per week and last for 3 months or longer.
- Slow wave sleep
(SWS). A stage of sleep, also known as deep sleep, that ischaracterized by synchronized electroencephalogram activity with the presence of slow waves, or delta wave activity. SWS is often viewed as a time of rest for neocortical neurons, in which the brain recovers from activities during the day.
- Circadian timing
In animals and humans, the sleep–wake cycle, which influences physiological processes including immunity, as well as levels of behavioural arousal.
- Sleep disturbance
For the purpose of this Review, a condition defined as insomnia complaints with daytime consequences, dissatisfaction with sleep quality or quantity, and/or insomnia disorder.
(EEG). A measure that tracks the electrical activity of the brain; one use is to graphically represent stages of sleep, which are defined by differences in waveform shape, frequency and amplitude.
(EMG). A measure that tracks the electrical activity of muscle; one use, together with the EEG, is to define stages of sleep, such as rapid eye movement sleep, in which there is low muscle tone or activity accompanied by random and rapid eye movements.
Bursts of oscillatory electroencephalogram activity that occur during stage 2 sleep, caused by a peak of electrical activity in one area of the brain followed by a peak of electrical activity in an adjacent area of the brain.
Large event waveforms of electroencephalogram activity that are considered to be a defining brainwave of stage 2 sleep. They are characterized by a brief negative peak of electrical activity, followed by a longer-duration positive complex and then another negative peak.
- Hypothalamic–pituitary–adrenal axis
(HPA axis). A neuroendocrine system that links the hypothalamus, pituitary and adrenal glands and functions to regulate the immune system in response to circadian signalling, behavioural states such as sleep and peripheral inflammatory signals.
- Sympathetic nervous system
(SNS). A component of the autonomic nervous system that comprises nerve fibres that innervate lymphoid tissues, as well as nearly all other body tissues. The SNS regulates immune cell traffic and immune responses during sleep and in response to stress through the release of noradrenaline.
- Circadian oscillator
Also known as the circadian clock. Cycles of oscillation are determined by biochemical signals and synchronized by solar time to influence 24-hour circadian timing in animals and in humans.
- Experimental sleep deprivation
Imposing a loss of sleep during the night, for either part of the night (in other words, partial night sleep deprivation) or for the entire night (in other words, total night sleep deprivation).
- Rapid eye movement sleep
(REM sleep). A stage of sleep, also known as paradoxical sleep, that is characterized by desynchronized electroencephalogram activity in a manner similar to waking, accompanied by random and rapid movement of the eyes together with low muscle tone. REM sleep is viewed as the sleep period in which there is a propensity to dream.
- IL-6 transignalling
The ability of IL-6 to form an agonistic complex with a soluble IL-6 receptor and thereby to activate cells that lack the membrane-bound IL-6 receptor, such as neural cells.
- Stress-induced sleep
A sleep-like state described in invertebrate models, in which a period of behavioural quiescence follows exposure to conditions that induce cellular stress, including exposure to tissue damage or extremes of temperature.
- Sleep duration
The amount of time spent asleep during the night, measured either by subjective report or objectively, using polysomnography or actigraphy. Short sleep duration is defined as less than the reference amount of 7 hours per night and is typically characterized as being less than 6 hours of sleep per night. Long sleep duration is typically characterized as being more than 8 hours of sleep per night.
Other animals belonging to the same species.
- Sleep continuity
The relative distribution of uninterrupted sleep, as opposed to wakefulness, during the night, as measured by sleep efficiency (time spent asleep as a percentage of the total time spent in bed) and wake time after sleep onset (the amount of time spent awake after turning off the lights and initiating sleep).
- C-reactive protein
(CRP). An acute phase protein that is synthesized by the liver in response to the production of IL-6 by macrophages or T cells.
Neuroendocrine hormones that belong to the steroid hormone class, which suppress inflammation and antiviral immune responses, in addition to having a role in the metabolism of protein, fat and glucose.
- Glucocorticoid resistance
A state of decreased sensitivity to the anti-inflammatory effects of glucocorticoids, which can be caused by ongoing increases in inflammation as well as by a genetic predisposition.
A component of the autonomic nervous system that comprises nerve fibres that innervate visceral tissues to regulate actions of the body when it is at rest, mainly through release of the neurotransmitter acetylcholine.
Increasing levels of systemic markers of inflammation during the usual ageing process.
- Cellular senescence
The state of a cell in which it is no longer able to replicate, which is also characterized by increased release of inflammatory mediators.
- Epigenetic age
An estimate of biological age given by evaluating changes in DNA methylation at particular genomic locations, which is found to be more predictive of mortality risk than is chronological age.
- Sleep consolidation
A sleep pattern characterized by high levels of sleep efficiency and low levels of awakening or sleep interruption.
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Irwin, M.R. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol 19, 702–715 (2019). https://doi.org/10.1038/s41577-019-0190-z
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