Acute sleep fragmentation induces tissue-specific changes in cytokine gene expression and increases serum corticosterone concentration

Abstract

Sleep deprivation induces acute inflammation and increased glucocorticosteroids in vertebrates, but effects from fragmented, or intermittent, sleep are poorly understood. Considering the latter is more representative of sleep apnea in humans, we investigated changes in proinflammatory (IL-1β, TNF-α) and anti-inflammatory (TGF-β1) cytokine gene expression in the periphery (liver, spleen, fat, and heart) and brain (hypothalamus, prefrontal cortex, and hippocampus) of a murine model exposed to varying intensities of sleep fragmentation (SF). Additionally, serum corticosterone was assessed. Sleep was disrupted in male C57BL/6J mice using an automated sleep fragmentation chamber that moves a sweeping bar at specified intervals (Lafayette Industries). Mice were exposed to bar sweeps every 20 s (high sleep fragmentation, HSF), 120 s (low sleep fragmentation, LSF), or the bar remained stationary (control). Trunk blood and tissue samples were collected after 24 h of SF. We predicted that HSF mice would exhibit increased proinflammatory expression, decreased anti-inflammatory expression, and elevated stress hormones in relation to LSF and controls. SF significantly elevated IL-1β gene expression in adipose tissue, heart (HSF only), and hypothalamus (LSF only) relative to controls. SF did not increase TNF-α expression in any of the tissues measured. HSF increased TGF-β1 expression in the hypothalamus and hippocampus relative to other groups. Serum corticosterone concentration was significantly different among groups, with HSF mice exhibiting the highest, LSF intermediate, and controls with the lowest concentration. This indicates that 24 h of SF is a potent inducer of inflammation and stress hormones in the periphery, but leads to upregulation of anti-inflammatory cytokines in the brain.

Novel environment influences the effect of paradoxical sleep deprivation upon brain and peripheral cytokine gene expression

“…In addition, there was an unanticipated elevation in anti-inflammatory cytokine (Tgfβ1) gene expression in the pre-frontal cortex. Previous work in our laboratory using a different method to induce sleep loss (horizontally-sweeping bar that moves across home cage at specified intervals to periodically awaken mice) also reported increased gene expression of pro-inflammatory (IL1, but not TNF) cytokines in the periphery and anti-inflammatory Tgfβ1 in brain [7]. Upregulation of anti-inflammatory cytokines may occur to homeostatically dampen inflammatory responses as a result of sleep deprivation and provide a protective effect, as prolonged inflammation can lead to tissue damage [2].…”

“…The cytokine probes were labeled with 5-FAM (5’ end) and the quencher MGB (3’ end). These probes were selected based upon previous sleep deprivation studies [7, 31]. The 18s control involved a Vic-labeled probe with MGB quencher.…”

“…Among animals that are sleep deprived, activation of the hypothalamic-pituitary-adrenal (HPA) axis is a common occurrence [7, 17, 18, 20], leading to the secretion of glucocorticoids from the adrenals. HPA activation from sleep loss is likely due to a multitude of factors that are related to the method of sleep deprivation employed (e.g., flower-pot, multiple platform, human handling, moving bar, etc.)…”

“…Specifically, it was predicted that 24 h of acute PSD would increase interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) pro-inflammatory gene expression and decrease transforming growth factor-beta-1 (TGFβ1) expression, an anti-inflammatory cytokine in peripheral tissues and brain (hippocampus, hypothalamus, pre-frontal cortex)-select areas previously shown to be sensitive to effects of sleep loss [7, 32]. In addition, it was further predicted that elevated plasma corticosterone would accompany these changes in immune responses.…”

Neuroendocrine-immune circuits, phenotypes, and interactions

“…Although pro-inflammatory cytokines, such as IL-1 and TNF, are typically associated with development of an inflammatory response (Ashley et al, 2012; Medzhitov, 2008), there is increasing evidence that these cytokines play a role in mediating physiological and behavioral processes in healthy animals. For example, cytokine secretion is tied to biological rhythms and the sleep/wake cycle (Opp, 2005), and experimental sleep loss leads to the induction of a pro-inflammatory response in brain and peripheral tissues (Ashley et al, 2016; Dumaine and Ashley, 2015; Faraut et al, 2012). Whether such an inflammatory response is adaptive (at the least in the short term) remains to be seen.…”