How (and why) the immune system makes us sleep

Abstract

Good sleep is necessary for physical and mental health. For example, sleep loss impairs immune function, and sleep is altered during infection. Immune signalling molecules are present in the healthy brain, where they interact with neurochemical systems to contribute to the regulation of normal sleep. Animal studies have shown that interactions between immune signalling molecules (such as the cytokine interleukin 1) and brain neurochemical systems (such as the serotonin system) are amplified during infection, indicating that these interactions might underlie the changes in sleep that occur during infection. Why should the immune system cause us to sleep differently when we are sick? We propose that the alterations in sleep architecture during infection are exquisitely tailored to support the generation of fever, which in turn imparts survival value.Modern sleep research began in 1953, with the discovery of rapid eye movement (REM) sleep and the realization that sleep is an active process that consists of two distinct phases. More than half a century of intense investigation has yet to provide an unequivocal answer to the question, 'Why do we sleep?' Nonetheless, we are beginning to understand the contribution of sleep to fundamental brain processes 1,2 .In contrast to our lack of knowledge regarding the precise functions of sleep, we do know why we have an immune system. Living organisms are subject to constant attack by various pathogens, and the complex networks of physical and biochemical components that constitute the immune system keep the organism alive. Like sleep research, the field of immunology is a relatively young discipline. It should therefore not come as a surprise that systematic investigations of interactions between sleep and the immune system have only been conducted in the past 25 years (TIMELINE). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAlthough we briefly touch on the general role of sleep in health and disease, in this Review we focus on those areas of research that are most relevant to sleep as a component of the host defence against microbial pathogens. Links between the CNS and the peripheral immune system are now well established, and much is known about the mechanisms by which bidirectional communication occurs between these systems 3 . As a result of neuro-immune interactions, sleep loss alters immune function and immune challenges alter sleep. Thus, chronic sleep loss results in pathologies that are associated with increases in inflammatory mediators, and inflammatory mediators that are released during immune responses to infection alter CNS processes and behaviour, including sleep.One class of immunomodulators, cytokines, has been extensively studied both with respect to host responses to infection and as regulators of physiological sleep. In this Review, we briefly summarize what is known about cytokines in the brain as regulators of normal, physiological sleep and what is known about their role in mediating the changes in sleep that are in...

Depression in Autoimmune Diseases

“…It is well established that rodents injected systemically or intacerebroventricularly with cytokines including TNF and IL-1 show an increase in sleep at times when mice are usually active (for review see (Imeri and Opp, 2009;Krueger, 2008)). NREM sleep was found to be increased in the …”

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…29,36,[73][74][75] In healthy humans, the levels of IL-1b in blood plasma are highest at the onset of sleep. 16,76 This and other evidence, including circadian control of the production of somnogenic cytokines, indicates their involvement in physiological sleep regulation. Activated processing and release of cytokines by microglia (brain phagocytes) is caused in part by rising levels of extracellular ATP during wakefulness.…”

“…56,65,66 As described below, these and other inflammatory cytokines can act as somnogens, indicating a major but incompletely understood connection between the immune system and sleep. 4,16,29,31,36,[67][68][69][70][71][72][73][74][75][76][77][78][79] Another potent endogenous somnogen is the PGD 2 prostaglandin, which preferentially induces NREM sleep. 11,28,80,81 The somnogenic activity of PGD 2 is mediated at least in part by the ability of brain-produced PGD 2 to increase the concentration of extracellular adenosine.…”

Cardiac Vagal Control and Depressive Symptoms: The Moderating Role of Sleep Quality

“…In the following, we will consider sleep quality as an important factor that may help explain the inconsistent links between CVC and depressive symptoms. Reduced sleep quality has emerged as an important risk factor in a variety of physical and mental health conditions including depression (see Imeri & Opp, 2009; Taylor, Lichstein, & Durrence, 2003), whereas high sleep quality may well have the potential to protect against elevated depressive symptoms in individuals with lower CVC.…”