Department of Biology, Western Kentucky University, Bowling Green, KY, United States of America.
PeerJ. 2024 Jun 28;12:e17539. doi: 10.7717/peerj.17539. eCollection 2024.
The association between sleep and the immune-endocrine system is well recognized, but the nature of that relationship is not well understood. Sleep fragmentation induces a pro-inflammatory response in peripheral tissues and brain, but it also activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) (cortisol in humans and corticosterone in mice). It is unclear whether this rapid release of glucocorticoids acts to potentiate or dampen the inflammatory response in the short term. The purpose of this study was to determine whether blocking or suppressing glucocorticoid activity will affect the inflammatory response from acute sleep fragmentation (ASF). Male C57BL/6J mice were injected i.p. with either 0.9% NaCl (vehicle 1), metyrapone (a glucocorticoid synthesis inhibitor, dissolved in vehicle 1), 2% ethanol in polyethylene glycol (vehicle 2), or mifepristone (a glucocorticoid receptor antagonist, dissolved in vehicle 2) 10 min before the start of ASF or no sleep fragmentation (NSF). After 24 h, samples were collected from brain (prefrontal cortex, hypothalamus, hippocampus) and periphery (liver, spleen, heart, and epididymal white adipose tissue (EWAT)). Proinflammatory gene expression (TNF- and IL-1) was measured, followed by gene expression analysis. Metyrapone treatment affected pro-inflammatory cytokine gene expression during ASF in some peripheral tissues, but not in the brain. More specifically, metyrapone treatment suppressed IL-1 expression in EWAT during ASF, which implies a pro-inflammatory effect of GCs. However, in cardiac tissue, metyrapone treatment increased TNF- expression in ASF mice, suggesting an anti-inflammatory effect of GCs. Mifepristone treatment yielded more significant results than metyrapone, reducing TNF- expression in liver (only NSF mice) and cardiac tissue during ASF, indicating a pro-inflammatory role. Conversely, in the spleen of ASF-mice, mifepristone increased pro-inflammatory cytokines (TNF- and IL-1), demonstrating an anti-inflammatory role. Furthermore, irrespective of sleep fragmentation, mifepristone increased pro-inflammatory cytokine gene expression in heart (IL-1), pre-frontal cortex (IL-1), and hypothalamus (IL-1). The results provide mixed evidence for pro- and anti-inflammatory functions of corticosterone to regulate inflammatory responses to acute sleep loss.
睡眠与免疫内分泌系统之间的关联已得到广泛认可，但它们之间的关系性质仍未得到很好的理解。睡眠碎片化会在外周组织和大脑中引发炎症反应，但它也会激活下丘脑-垂体-肾上腺 (HPA) 轴，释放糖皮质激素（GCs）（人类为皮质醇，小鼠为皮质酮）。目前尚不清楚这种快速释放的糖皮质激素是否会在短期内增强或抑制炎症反应。本研究旨在确定阻断或抑制糖皮质激素活性是否会影响急性睡眠碎片化 (ASF) 引起的炎症反应。雄性 C57BL/6J 小鼠在 ASF 开始前 10 分钟通过腹腔注射给予 0.9% NaCl（载体 1）、美替拉酮（一种糖皮质激素合成抑制剂，溶于载体 1）、2%乙醇在聚乙二醇中（载体 2）或米非司酮（一种糖皮质激素受体拮抗剂，溶于载体 2），或不进行睡眠碎片化（NSF）。24 小时后，从大脑（前额叶皮层、下丘脑、海马体）和外周组织（肝脏、脾脏、心脏和附睾白色脂肪组织 (EWAT)）采集样本。测量促炎基因表达（TNF-α 和 IL-1），然后进行基因表达分析。美替拉酮处理影响了一些外周组织在 ASF 期间的促炎细胞因子基因表达，但对大脑没有影响。更具体地说，美替拉酮处理抑制了 ASF 期间 EWAT 中的 IL-1 表达，这意味着 GCs 具有促炎作用。然而，在心脏组织中，美替拉酮处理增加了 ASF 小鼠 TNF-α 的表达，表明 GCs 具有抗炎作用。米非司酮处理比美替拉酮处理产生了更显著的结果，降低了 ASF 期间肝脏（仅 NSF 小鼠）和心脏组织中 TNF-α 的表达，表明其具有促炎作用。相反，在 ASF 小鼠的脾脏中，米非司酮增加了促炎细胞因子（TNF-α 和 IL-1）的表达，表明其具有抗炎作用。此外，无论是否发生睡眠碎片化，米非司酮均增加了 ASF 期间心脏（IL-1）、前额叶皮层（IL-1）和下丘脑（IL-1）中促炎细胞因子基因的表达。结果为皮质酮调节急性睡眠剥夺后炎症反应的促炎和抗炎功能提供了混合证据。
