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

Abstract

Sleep is a recuperative process, and its dysregulation has cognitive, metabolic, and immunological effects that are largely deleterious to human health. Epidemiological and empirical studies have suggested that sleep fragmentation (SF) as result of obstructive sleep apnea (OSA) and other sleep abnormalities leads to pronounced inflammatory responses, which are influenced by the sympathetic nervous system (SNS). However, the underlying molecular mechanisms contributing to SNS regulation of SF-induced inflammation are not fully understood. To assess the effects of the SNS upon inflammatory responses to SF, C57BL/6j female mice were placed in automated SF chambers with horizontally moving bars across the bottom of each cage at specified intervals to disrupt sleep. Mice were first subjected to either control (no bar movement), acute sleep fragmentation (ASF), or chronic sleep fragmentation (CSF) on a 12:12-h light/dark schedule. ASF involved a bar sweep every 120 s for 24 h, whereas CSF involved a bar sweep every 120 s for 12 h (during 12 L; resting period) over a period of 4 weeks. After exposure to these conditions, mice received an intraperitoneal injection of either phentolamine (5 mg/kg BW; an α-adrenergic receptor blocker), propranolol (5 mg/kg BW; a β-adrenergic receptor blocker), or vehicle (saline). Serum corticosterone concentration, brain and peripheral cytokine (IL1β, TNFα, and TGFβ) mRNA expression, and body mass were assessed. ASF and CSF significantly elevated serum corticosterone concentrations as well as cytokine mRNA expression levels compared with controls, and mice subjected to CSF had decreased body mass relative to controls. Mice subjected to CSF and treated with phentolamine or propranolol had a greater propensity for a decrease in cytokine gene expression compared with ASF, but effects were tissue-specific. Taken together, these results suggest that both α- and β-adrenergic receptors contribute to the SNS mediation of inflammatory responses, and adrenergic antagonists may effectively mitigate tissue-specific SF-mediated inflammation.

Inflammation from Sleep Fragmentation Starts in the Periphery Rather than Brain in Male Mice

“…The brain responses for IL-1β gene expression were similar compared to TNFα but earlier. These results are a departure from previous studies that have shown elevated pro-in ammatory gene expression in hypothalamus, hippocampus, and pre-frontal cortex after 24-h of sleep fragmentation among female C57BL/6J mice 17,18 , but very few effects observed among males 10,23 , although there was a non-signi cant trend for increased pro-in ammatory gene expression in hippocampus in one study 12 . Reasons for this discrepancy are unclear, but could involve differences in how hippocampus was extracted from the brain in these different studies (whole vs. partial dissection).…”

“…The ndings indicate that pro-in ammatory responses to acute sleep fragmentation are tissue-speci c, which is consistent with previous studies [16][17][18]23 . ASF increased TNFα expression in heart and EWAT after exposure for 12 and 24 h, respectively, but there was no effect in liver or spleen.…”

“…The alternative hypothesis is that in ammation begins in the periphery with sympathetic afferents relaying this information to the brain, similar to a neuro-immune re ex to peripheral immune challenge 15 . As evidence, previous studies have shown that inhibition of the peripheral sympathetic nervous system (SNS) reduces in ammatory responses to SF in peripheral tissues 16,17 and brain 18 .…”

Role of sleep deprivation in immune-related disease risk and outcomes

“…Although the specific role of SNS activation in the immune phenotype associated with sleep deprivation is not clearly established, data suggest a proinflammatory effect of SNS under sleep deprivation. Indeed, chemical sympathectomy has been recently shown to alleviate the inflammatory response following chronic sleep deprivation in mice 255 , and both αand, to a lesser extent, β-adrenergic receptors seem to contribute to the sympathetic regulation of inflammatory responses to sleep deprivation 256 .…”

Contrasting effects of sleep fragmentation and angiotensin-II treatment upon pro-inflammatory responses of mice

“…It has been proposed that alterations in these immunoregulatory hormones may contribute to this pro-inflammatory phenotype 14 . This hypothesis has received empirical support using chemical sympathectomy and pharmacological blockade of adrenergic receptors to demonstrate that SNS suppression ameliorates inflammation from experimental sleep fragmentation in mice 15 , 16 . An additional hypothesis to explain inflammation from sleep loss involves vascular changes associated with increased blood pressure as a result of increased sympathetic output from prolonged wakefulness 14 , 17 .…”