Chemical sympathectomy reduces peripheral inflammatory responses to acute and chronic sleep fragmentation

Abstract

Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorders by promoting a systemic proinflammatory phenotype. The neuroendocrine-immune mechanisms contributing to such pathologies are poorly understood. The sympathetic nervous system (SNS) regulates immunity and is often activated following sleep disturbances. The aims of this study were to determine 1) the effect of SNS inhibition on inflammatory responses to sleep fragmentation (SF) and 2) whether homeostasis can be restored after 1 wk of recovery sleep. We measured stress responses (norepinephrine and corticosterone), gene expression levels of pro- and anti-inflammatory cytokines in peripheral (heart, liver, and spleen) tissues, and protein levels of cytokines and chemokines in serum of female mice that were subjected to acute SF for 24 h, chronic SF for 8 wk, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were chemically sympathectomized with 6-hydroxydopamine (6-OHDA) or injected with vehicle. Both acute and chronic SF elevated mRNA and protein levels of cytokines in peripheral tissues. Changes in inflammatory responses mirrored stress-axes activation, with increased corticosterone and norepinephrine in SF mice. 6-OHDA treatment significantly alleviated SF-induced inflammation, thus providing evidence of SNS regulation of peripheral inflammation from SF. Effects of chronic SF were more severe than acute SF, and 1 wk of recovery from SF sufficiently alleviated peripheral inflammatory responses but not NE responses.

Alpha- and beta- adrenergic receptors regulate inflammatory responses to acute and chronic sleep fragmentation in mice

“…While effects of acute sleep loss on SNS and HPA activity can be considered mild or adaptive, chronic sleep loss caused by OSA, shift work, and modern lifestyles can contribute to more deleterious effects such as cardiovascular and metabolic disease, obesity and neurological disorders (Schwartz et al, 1999;Mavanji et al, 2012). Our laboratory previously showed that SF-induced increases in cytokine gene expression and serum proteins were mitigated by chemical sympathectomy, confirming that inhibition of the SNS reduces inflammatory responses from acute and chronic SF (Mishra et al, 2020). However, it is unknown how NE is acting on these target tissues to regulate inflammation.…”

“…The following protocols were described previously by Mishra et al (2020). Briefly, RNA was extracted from EOWAT, heart, liver, spleen, and brain tissue using RNeasy mini kits (Qiagen).…”

“…Dysregulated sleep and OSA are associated with increased circulating concentrations of proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α (Faraut et al, 2012), which are important molecular signatures of a pro-inflammatory response (Ashley, Weil & Nelson, 2012). The progressive build-up of inflammatory insults can promote a systemic chronic inflammatory state that can lead to cardiovascular and metabolic disease, as well as cancer and neurogenerative disorders (Straub & Schradin, 2016;Furman et al, 2019) It is well known that hormonal responses regulate inflammatory responses (Silverman & Sternberg, 2012;Cain & Cidlowski, 2017); however, there are few empirical studies investigating these responses within the context of sleep loss (see Mishra et al, 2020). The activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) are commonly identified as physiological stress responses (Suchecki et al, 1998;Meerlo, Sgoifo & Suchecki, 2008), and can be triggered by sleep restriction or deprivation.…”

“…The activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) are commonly identified as physiological stress responses (Suchecki et al, 1998;Meerlo, Sgoifo & Suchecki, 2008), and can be triggered by sleep restriction or deprivation. Sleep curtailment can increase SNS activity and subsequently an elevation of norepinephrine (NE) released through noradrenergic neurons and epinephrine and NE from the adrenal medullae (Dimsdale et al, 1995;Tiemeier et al, 2002;Mishra et al, 2020). Glucocorticoids are released from adrenal cortices via HPA activation (Suchecki et al, 1998;Meerlo, Sgoifo & Suchecki, 2008) several minutes after SNS stimulation.…”

“…Brain and peripheral tissues will be assessed for cytokine gene expression, specifically the hypothalamus, hippocampus, and prefrontal cortex (for brain) and spleen, white adipose tissue, liver, and heart (for periphery). These regions were selected based upon past studies that have reported an inflammatory response in those specific tissues from sleep fragmentation (Dumaine & Ashley, 2015;Mishra et al, 2020).…”