Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

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.

Figure 1

Sleep disturbance and innate immunity. Following a night of sleep loss, or during a period of sleep disturbance, nerve fibers from the SNS release the neurotransmitter norepinephrine into primary and secondary lymphoid organs and stimulate the adrenal gland to release stored epinephrine into the systemic circulation. Both neuromediators stimulate leukocyte adrenergic receptors (eg, ADRB2) and activate nuclear factor (NF)-κB-mediated inflammatory programs. Intrinsic circuits detect microbes via pattern recognition receptors (PRRs) such as the toll-like receptor 4 (TLR4) and stimulate inflammatory gene expression via transcription factors such as nuclear factor (NF)-κB. The production of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) occurs. Bidirectional links between the brain and periphery allow the brain to regulate inflammatory activity, and inflammatory activity in turn can influence neural processes in the brain and alter sleep. When this dynamic is induced by sustained sleep disturbance, a feed-forward dysregulation of sleep can occur, which may also confer activation of the conserved transcriptional response to adversity (CTRA). CTRA activation leads to increases in proinflammatory gene expression and increased risk for inflammation-related disorders such as cardiovascular disease, cancer, and major depressive disorder, and to decreases in antiviral gene expression and increased risk of infectious diseases.

Figure 2

Associations between sleep efficiency and evening (a) and morning (b) levels of stimulated monocytic expression of TNF in RA patients and controls, as illustrated by estimated regression lines by group, controlling for depressive symptoms and physical health functioning. Curvilinear brackets indicate residual standard error. For stimulated production of TNF, results are presented as % of total number of monocytes expressing TNF, respectively, natural log-transformed.

Figure 3

Representative expression of IL-6 and TNF in LPS-stimulated CD14+ cells from a participant at baseline and at PSD. Numbers indicate percentage of the fraction of CD14+ cells that are positive for TNF alone (upper left), TNF and IL-6 (upper right), and IL-6 alone (lower right). In the baseline condition, 72.1% of the CD14+ cells are negative for both IL-6 and TNF, whereas only 34.5% of the CD14+ cells are negative for both IL-6 and TNF in the PSD condition.

Figure 4

Effects of sleep disturbance and extremes of sleep duration on cellular and molecular processes of inflammation including activation of NF-κB, inflammatory gene expression, production of proinflammatory cytokines, and increase in systemic inflammation as indexed by C-reactive protein (CRP).

Figure 5

Forest plot of sleep disturbance associated with inflammation as indexed by C-reactive protein. Sleep disturbance is assessed by self-reported symptoms and questionnaires. Results are expressed as ES and 95% CI.

Figure 6

Mean CRP level at follow-up according to baseline sleep disturbance score in socially integrated (n=1502) and socially isolated (n=1460) subgroups. Error bars represent SEM.

Figure 7

Estimated mean and standard error of multisystem biological risk by sleep duration and PSQI global sleep score. Mean and standard error estimates derived from model after adjustments by age, gender, race, BMI, education, income poverty ratio, chronic conditions, and self-evaluated physical health. Multisystem Biological Risk score ranged from 0 to 7.

Figure 8

Gene expression of the SASP and DDR at baseline, PSD, and 1 day after PSD (recovery). SASP is a composite score created from a sum of nine z-transformed genes. DDR is a composite score created from a sum of 30 z-transformed genes. Error bars represent standard error of estimated marginal mean, adjusting for BMI and sex. *p<0.05.

Figure 9

Effect of endotoxin on depressed mood over time in females according to sleep disturbance. Depressed mood was assessed at baseline (T0) and then approximately every hour after injection for the next 6 h (T1–T6). T2 was assessed at 1 h and 40 min after injection; T3 was assessed at 3 h and 30 min after injection; and T4–T6 were assessed hourly after T3. Error bars indicate 95% confidence intervals. *Marginal means adjusted for age, race, BMI, and baseline depressive symptoms.

Figure 10

Interleukin 1 and serotonin interact at multiple sites in the brain to regulate NREM sleep. A schematic representation of interactions in the brain among interleukin 1 (IL-1), serotonin (also known as 5-hydroxytryptamine (5-HT)), and γ-aminobutyric acid (GABA) that are relevant for the regulation of NREM sleep. In the dorsal raphe nuclei (DRN), where IL-1 microinjections promote NREM sleep, IL-1 reduces the firing rate of wake-active serotonergic neurons by enhancing the inhibitory effects of GABA. In the hypothalamic preoptic area/basal forebrain region (POA/BF), IL-1 stimulates 5-HT release from axon terminals. 5-HT, in turn, inhibits cholinergic neurons involved in cortical activation and stimulates the synthesis of IL-1, which inhibits wake-promoting neurons and activates a subset of sleep-promoting neurons in the POA/BF. IL-1 in the POA/BF is under potent inhibitory homeostatic control by corticosteroids released into the blood by the adrenal cortex. Corticosteroid levels depend on the activity of the hypothalamic–pituitary–adrenal axis, which is stimulated by activation of the 5-HT system. ACh, acetylcholine; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; IPSP, inhibitory postsynaptic potential; PVN, paraventricular nucleus of the hypothalamus.

Figure 11

Estimated PSQI levels (±SE) before and after intervention. Significant (P=0.002) differences were found between groups covarying for pre-intervention PSQI score; PSQI, Pittsburgh Sleep Quality Index.

Figure 12

Toll-like 4 Receptor Stimulated Monocytic Production from Baseline to Month 16, by Treatment Group. Values are mean (SEM) percentage of monocytes producing IL-6 (a), TNF (b); or both IL-6 and TNF (c). Shaded area indicates period of administration of intervention following baseline assessment. Significant pairwise comparisons: CBT vs SS P<0.05; TCC vs SS P<0.05, CBT vs TCC P<0.05.

Figure 13

Transcription factor activity as measured by TELiS promoter-based bioinformatic analyses of genes at 4 months (post intervention), showing differential change in gene expression for comparisons of CBT vs SS, and TCC vs SS.