Role of sleep deprivation in immune-related disease risk and outcomes
睡眠剥夺在免疫相关疾病风险和结局中的作用

Abstract 抽象

Introduction 介绍

Sleep is an active physiological process necessary for life and normally occupying one-third of our lives, playing a fundamental role for physical, mental, and emotional health¹. Sleep patterns and need are influenced by a complex interplay between chronological age, maturation stage, genetic, behavioral, environmental, and social factors^2–6. Adults should sleep a minimum of 7 h per night to promote optimal health^7,8.
睡眠是生命所必需的活跃生理过程，通常占据我们生命的三分之一，对身体、心理和情绪健康 ¹ 起着重要作用。睡眠模式和需求受到实际年龄、成熟阶段、遗传、行为、环境和社会因素 ^2–6 之间复杂相互作用的影响。成年人每晚应至少睡 7 小时，以促进最佳健康 ^7,8 。

Besides medical problems including obstructive sleep apnea and insomnia, factors associated mostly with the modern 24/7 society, such as work and social demands, smartphone addiction, and poor diet^9–11, contribute to cause the current phenomenon of chronic sleep deprivation, i.e., sleeping less than the recommended amount or, better to say, the intrinsic sleep need¹².
除了阻塞性睡眠呼吸暂停和失眠等医疗问题外，主要与现代 24/7 社会相关的因素，例如工作和社会需求、智能手机成瘾和不良饮食 ^9–11 习惯，导致当前慢性睡眠剥夺现象，即睡眠少于推荐量，或者更好地说，内在睡眠需求 ¹² 。

Sleep deprivation may be categorized as acute or chronic. Acute sleep deprivation refers to no sleep or reduction in the usual total sleep time, usually lasting 1–2 days, with waking time extending beyond the typical 16–18 h. Chronic sleep deprivation is defined by the Third Edition of the International Classification of Sleep Disorders as a disorder characterized by excessive daytime sleepiness caused by routine sleeping less than the amount required for optimal functioning and health maintenance, almost every day for at least 3 months¹³.
睡眠剥夺可分为急性或慢性。急性睡眠剥夺是指没有睡眠或通常的总睡眠时间减少，通常持续 1-2 天，清醒时间超过典型的 16-18 小时。国际睡眠障碍分类第三版将慢性睡眠剥夺定义为一种以日常睡眠少于最佳功能和健康维持所需量而引起的白天过度嗜睡的疾病，几乎每天至少持续 3 个月 ¹³ 。

Population studies reported a stably increasing prevalence of adults sleeping less than 6 h per night over a long period^12,14,15, also affecting children and adolescents^16,17. Sleep duration decline is present not only in high-income and developed countries¹⁸ but also in low-income or racial/ethnic minorities¹⁹, thus representing a worldwide problem.
人口研究报告称 ^12,14,15 ，成年人在很长一段时间内每晚睡眠时间少于6小时的患病率稳步上升，这也影响了儿童和青少年 ^16,17 。睡眠时间下降不仅存在于高收入和发达国家 ¹⁸ ，也存在于低收入或种族/少数民族 ¹⁹ 中，因此是一个世界性问题。

In addition to fatigue, excessive daytime sleepiness, and impaired cognitive and safety-related performance, sleep deprivation is associated with an increased risk of adverse health outcomes and all-cause mortality^20–24. Indeed, epidemiological and experimental data support the association of sleep deprivation with the risk of cardiovascular (CV) (hypertension and coronary artery disease) and metabolic (obesity, type 2 diabetes (T2DM)) diseases^24–27. In the United States, sleep deprivation has been linked to 5 of the top 15 leading causes of death including cardio- and cerebrovascular diseases, accidents, T2DM, and hypertension²⁸. Data also point to a role for sleep deprivation in the risk of stroke, cancer, and neurodegenerative diseases (NDDs)^26,29,30. Sleep deprivation is also associated with psychopathological and psychiatric disorders, including negative mood and mood regulation, psychosis, anxiety, suicidal behavior, and the risk for depression^31–36.
除了疲劳、白天过度嗜睡以及认知和安全相关表现受损外，睡眠不足还与不良健康结果和全因死亡率 ^20–24 的风险增加有关。事实上，流行病学和实验数据支持睡眠不足与心血管 （CV）（高血压和冠状动脉疾病）和代谢（肥胖、2 型糖尿病 （T2DM））疾病 ^24–27 的风险相关联。在美国，睡眠不足与前 15 大主要死因中的 5 种有关，包括心脑血管疾病、事故、T2DM 和高血压 ²⁸ 。数据还指出，睡眠不足在中风、癌症和神经退行性疾病 （NDD） ^26,29,30 的风险中起着重要作用。睡眠不足还与精神病理学和精神疾病有关，包括负面情绪和情绪调节、精神病、焦虑、自杀行为和抑郁症 ^31–36 的风险。

Both too short or too long sleep durations have been found to be associated with adverse health outcomes and all-cause mortality with an U-shaped relationship^37–39. Although the relation of long sleep duration to adverse health outcomes may be confounded by poor health conditions occurring in older adults³⁷, the causal association of sleep deprivation with negative health effects is substantiated by experimental evidence providing biological plausibility^24,40,41.
已发现睡眠时间过短或过长都与不良健康结果和全因死亡率有关，呈 U 形关系 ^37–39 。虽然长睡眠时间与不良健康结果的关系可能被老年人的不良健康状况所混淆 ³⁷ ，但睡眠剥夺与负面健康影响的因果关系得到了提供生物学合理性的实验证据的证实 ^24,40,41 。

Sleep profoundly affects endocrine, metabolic, and immune pathways, whose dysfunctions play a determinant role in the development and progression of chronic diseases^42–44. Specifically, in many chronic diseases, a deregulated/exacerbated immune response shifts from repair/regulation towards unresolved inflammatory responses⁴⁵.
睡眠深刻影响内分泌、代谢和免疫途径，其功能障碍在慢性疾病 ^42–44 的发展和进展中起着决定性作用。具体来说，在许多慢性疾病中，失调/加剧的免疫反应从修复/调节转变为未解决的炎症反应 ⁴⁵ 。

Regular sleep is crucial for maintaining immune function integrity and favoring a homeostatic immune defense to microbial or inflammatory insults^46,47. Sleep deprivation may result in deregulated immune responses with increased pro-inflammatory signaling, thus contributing to increase the risk for the onset and/or worsening of infection, as well as inflammation-related chronic diseases.
规律的睡眠对于维持免疫功能完整性和有利于对微生物或炎症损伤的稳态免疫防御至关重要 ^46,47 。睡眠不足可能导致免疫反应失调，促炎信号增加，从而增加感染发作和/或恶化的风险，以及与炎症相关的慢性疾病。

Here we reviewed the evidence regarding the impact of sleep deprivation on immune-related diseases by discussing the major points as follows: (1) the immune–sleep relationship; (2) the association of sleep deprivation with the development and/or progression of immune-related chronic diseases; and (3) the immune consequences of sleep deprivation and their implications for diseases. Finally, possible measures to reverse sleep deprivation-associated immune changes were discussed.
在这里，我们回顾了关于睡眠剥夺对免疫相关疾病影响的证据，讨论了以下要点：（1）免疫-睡眠关系;（2）睡眠不足与免疫相关慢性疾病的发展和/或进展的关联;（3）睡眠不足的免疫后果及其对疾病的影响。最后，讨论了逆转睡眠剥夺相关免疫变化的可能措施。

Basic immune mechanisms of sleep regulation
睡眠调节的基本免疫机制

The discovery of muramyl peptide, a bacterial cell wall component that is able to activate the immune system and induce the release of sleep-regulatory cytokines, primary regulators of the inflammatory system, provided the first molecular link between the immune system and sleep⁴⁸. Thereafter, other microbial-derived factors such as the endotoxin lipopolysaccharide (LPS)⁴⁹, as well as mediators of inflammation, such as the cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α, prostaglandins (PGs), growth hormone-releasing hormone (GHRH), and growth factors, were recognized as sleep-regulating factors⁵⁰.
胞壁肽是一种细菌细胞壁成分，能够激活免疫系统并诱导睡眠调节细胞因子（炎症系统的主要调节因子）的释放，发现了免疫系统和睡眠 ⁴⁸ 之间的第一个分子联系。此后，其他微生物衍生因子如内毒素脂多糖 （LPS） ⁴⁹ 以及炎症介质，如细胞因子白细胞介素 （IL）-1 和肿瘤坏死因子 （TNF）-α、前列腺素 （PG）、生长激素释放激素 （GHRH） 和生长因子，被认为是睡眠调节因 ⁵⁰ 子。

Along this line, most animal studies have consistently shown a role in particular for IL-1, TNF-α, and PGD₂ in the physiologic, homeostatic non-rapid eye movement (NREM) sleep regulation, so that the inhibition of their biological action resulted in decreased spontaneous NREM sleep, whereas their administration enhanced NREM sleep amount and intensity, and suppressed rapid eye movement (REM) sleep^51–53. Moreover, the circulating levels of IL-1, IL-6, TNF-α, and PGD₂ are highest during sleep⁵⁴. Their effects are dose- and time-of-day-dependent so that, for instance, low doses of IL-1 enhance NREMS, whereas high doses inhibit sleep⁵⁵. Reciprocal effects may be involved in sleep regulation: for instance, the effects of systemic bacterial products such as LPS may also involve TNF-α⁴⁹. Links exist between IL-1β and GHRH/growth hormone (GH) in promoting sleep so that IL-1 induced GH release via GHRH⁵⁶, and hypothalamic γ-aminobutyric acid (GABA)ergic neurons (promoting sleep) are responsive to both GHRH and IL-1β⁵⁷. Instead, anti-inflammatory cytokines, including IL-4, IL-10, and IL-13, inhibited NREM sleep in animal models⁵⁸.
沿着这个思路，大多数动物研究一致表明，IL-1、TNF-α 和 PGD ₂ 在生理、稳态非快速眼动 （NREM） 睡眠调节中特别起作用，因此抑制它们的生物作用导致自发性 NREM 睡眠减少，而它们的给药增强了 NREM 睡眠量和强度，并抑制了快速眼动 （REM） 睡眠 ^51–53 。此外，IL-1、IL-6、TNF-α 和 PGD ₂ 的循环水平在睡眠 ⁵⁴ 期间最高。它们的作用与剂量和一天中的时间有关，因此，例如，低剂量的IL-1会增强NREMS，而高剂量会抑制睡眠 ⁵⁵ 。睡眠调节可能涉及相互效应：例如，LPS等全身细菌产物的影响也可能涉及TNF-α ⁴⁹ 。IL-1β 和 GHRH/生长激素 （GH） 之间存在促进睡眠的联系，因此 IL-1 通过 GHRH ⁵⁶ 诱导 GH 释放，并且下丘脑γ-氨基丁酸 （GABA） 能神经元（促进睡眠）对 GHRH 和 IL-1β 都有反应 ⁵⁷ 。相反，抗炎细胞因子，包括 IL-4、IL-10 和 IL-13，抑制了动物模型 ⁵⁸ 中的 NREM 睡眠。

Through these substances, the immune system may signal to the brain and interact with other factors involved in sleep regulation such as neurotransmitters (acetylcholine, dopamine, serotonin, norepinephrine, and histamine), neuropeptides (orexin), nucleosides (adenosine), the hormone melatonin, and the hypothalamus-pituitary axis (HPA) axis. Signaling mechanisms to the brain also involve vagal afferents: for instance, vagotomy attenuates intraperitoneal TNF-α-enhanced NREMS responses⁵⁹.
通过这些物质，免疫系统可以向大脑发出信号，并与参与睡眠调节的其他因素相互作用，例如神经递质（乙酰胆碱、多巴胺、血清素、去甲肾上腺素和组胺）、神经肽（食欲素）、核苷（腺苷）、褪黑激素和下丘脑-垂体轴 （HPA） 轴。大脑的信号传导机制也涉及迷走神经传入：例如，迷走神经切开术可减弱腹膜内 TNF-α 增强的 NREMS 反应 ⁵⁹ 。

Cytokines are produced by a vast array of immune cells, including those resident in the central nervous system (CNS), and non-immune cells, e.g., neurons, astrocytes and microglia, and peripheral tissue cells^60,61. Cytokines interact with the brain through humoral, neural, and cellular pathways, and form a brain cytokine network (Fig. 1) able to produce cytokines, their receptors, and amplify cytokine signals⁵⁰. Peripheral cytokines reach the brain through different non-exclusive mechanisms, including blood–brain barrier (BBB) disruption⁶², penetration of peripheral immune cells, and via afferent nerve fibers, such as the vagus nerve, a bundle of parasympathetic sensory fibers that conveys information from peripheral organs to the CNS⁶³.
细胞因子由大量免疫细胞产生，包括驻留在中枢神经系统 （CNS） 中的免疫细胞和非免疫细胞，例如神经元、星形胶质细胞和小胶质细胞以及外周组织细胞 ^60,61 。细胞因子通过体液、神经和细胞途径与大脑相互作用，形成脑细胞因子网络（图1），能够产生细胞因子及其受体并放大细胞因子信号 ⁵⁰ 。外周细胞因子通过不同的非排他性机制到达大脑，包括血脑屏障 （BBB） 破坏 ⁶² 、外周免疫细胞的渗透，以及通过传入神经纤维（例如迷走神经），迷走神经是一束副交感神经感觉纤维，将信息从外周器官传递到中枢神经系统 ⁶³ 。

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Fig. 1 图1

Brain cytokines (CYT, orange circles) network and different suggested routes by which peripherally released inflammatory signals can bypass the blood–brain barrier and circumventricular organs (CVOs), and activate the central nervous system: humoral, cellular, and neural pathways.
脑细胞因子（CYT，橙色圆圈）网络和不同的建议途径，通过这些途径，外周释放的炎症信号可以绕过血脑屏障和脑室周围器官 （CVO），并激活中枢神经系统：体液、细胞和神经通路。

CCL-2: C-C motif chemokine ligand-2; CXCL-10: C-X-C motif chemokine ligand 10; IL-1: interleukin-1; mNTS: medial nucleus tractus solitarius; PGE₂: prostaglandin E2; TNF-α: tumor necrosis factor-α.
CCL-2：C-C基序趋化因子配体-2;CXCL-10：C-X-C基序趋化因子配体10;IL-1：白细胞介素-1;mNTS：孤束内侧核;铂族元素 ₂ ：前列腺素E2;TNF-α：肿瘤坏死因子-α。

In the CNS, cytokines mediate a multiplicity of immunological and nonimmunologic biological functions⁶⁴, such as synaptic scaling, synapse formation and elimination, de novo neurogenesis, neuronal apoptosis, brain development, cortical neuron migration⁶⁵, circuit homeostasis and plasticity⁶⁶, and cortical neuron migration⁶⁵, and complex behaviors, sleep, appetite, aging, learning and memory⁶⁵, and mental health status^67,68.
在中枢神经系统中，细胞因子介导多种免疫和非免疫生物学功能 ⁶⁴ ，如突触缩放、突触形成和消除、从头神经发生、神经元凋亡、大脑发育、皮质神经元迁移 ⁶⁵ 、回路稳态和可塑性 ⁶⁶ 、皮质神经元迁移 ⁶⁵ 、复杂行为、睡眠、食欲、衰老、学习和记忆 ⁶⁵ 以及心理健康状况 ^67,68 。

A common experimental finding is that after damage to any brain area, if the animal or human survives, sleep always ensues⁶⁹. Recent evidence indicates that sleep is a self-organizing emergent neuronal/glial network property of any viable network regardless of size or location, whether in vivo or in vitro^53,70–73. Several sleep-regulatory substances, e.g., TNF, IL-1, nitric oxide, PGs, and adenosine are all produced within local cell circuits in response to cell use^74,75.
一个常见的实验发现是，在任何大脑区域受损后，如果动物或人类幸存下来，睡眠总是随之而来 ⁶⁹ 。最近的证据表明，睡眠是任何可行网络的自组织新兴神经元/神经胶质网络特性，无论其大小或位置如何，无论是在体内还是在体外 ^53,70–73 。几种睡眠调节物质，例如 TNF、IL-1、一氧化氮、PG 和腺苷，都是在局部细胞回路内产生的，以响应细胞的使用 ^74,75 。

From this point of view, TNF-α and IL-1 are closely interconnected and play a similar role in the regulation of sleep^76–81. IL-1β and TNF-α self-amplify and increase each other’s mRNA expression in the brain⁸². In rats, IL-1⁸³ and TNF-α⁸⁴ mRNAs show diurnal variations in different brain areas, with the highest concentrations recorded during increased sleep propensity and peaks occurring at time of sleep period onset in rats and mice⁸⁵.
从这个角度来看，TNF-α和IL-1密切相关，在调节睡眠 ^76–81 中起着相似的作用。IL-1β 和 TNF-α 自我扩增并增加彼此在大脑 ⁸² 中的 mRNA 表达。在大鼠中，IL-1 ⁸³ 和TNF-α ⁸⁴ mRNA在不同的大脑区域显示出昼夜变化，在大鼠和小鼠的睡眠倾向增加期间记录的最高浓度和峰值出现在睡眠期开始时 ⁸⁵ 。

Sleep-like states in mixed cultures of neurons and glia are dependent in part on the IL-1 receptor accessory protein (AcP)^69,86. In the brain, there is an AcP isoform, neuron-specific (AcPb)⁸⁷, whose mRNA levels increase with sleep loss^88,89. AcPb is anti-inflammatory, whereas AcP is pro-inflammatory^87,88.
神经元和神经胶质细胞混合培养物中的睡眠样状态部分依赖于 IL-1 受体辅助蛋白 （AcP）。 ^69,86 在大脑中，有一种 AcP 亚型，神经元特异性 （AcPb） ⁸⁷ ，其 mRNA 水平随着睡眠不足 ^88,89 而增加。AcPb 具有抗炎作用，而 AcP 具有促炎作用 ^87,88 。

TNF signaling promotes sleep, whereas reverse TNF-α signaling (the soluble TNF receptor) promotes waking⁹⁰. The brain production of TNF-α is neuron activity-dependent⁹¹. Afferent activity into the somatosensory cortex enhances TNF expression⁹², and in vitro optogenetic stimulation enhances neuronal expression of TNF immunoreactivity⁹³.
TNF 信号转导促进睡眠，而反向 TNF-α 信号转导（可溶性 TNF 受体）促进清醒 ⁹⁰ 。TNF-α的大脑产生是神经元活动依赖 ⁹¹ 性的。进入躯体感觉皮层的传入活动增强了TNF的表达 ⁹² ，体外光遗传学刺激增强了TNF免疫反应性的 ⁹³ 神经元表达。

Peripheral immune activation following acute or chronic infection or inflammatory diseases is marketed by altered cytokine concentrations and profiles, and is transmitted to the CNS initiating specific adaptive responses. Among these, a sleep response is induced and has been hypothesized to favor recovery from infection and inflammation, supposedly via the timely functional investment of energy into the energy-consuming immune processes^54,94. Accordingly, acute mild immune activation enhances NREM sleep and suppresses REM sleep, whereas severe immune response with an upsurge of cytokine levels causes sleep disturbance with the suppression of both NREM and REM sleep^49,95–98. This sleep change correlates to the course of the host immune response as observed in bacterial and Trypanosoma infections^97,99. Supportively, the increase in NREM sleep was a favorable prognostic factor for rabbits during infectious diseases⁹⁶.
急性或慢性感染或炎症性疾病后的外周免疫激活通过改变细胞因子浓度和谱进行销售，并传递到中枢神经系统，启动特异性的适应性反应。其中，诱导睡眠反应，并被假设有利于从感染和炎症中恢复，据说是通过及时将能量功能投入到消耗能量的免疫过程中 ^54,94 。因此，急性轻度免疫激活可增强 NREM 睡眠并抑制 REM 睡眠，而细胞因子水平激增的严重免疫反应会导致睡眠障碍，同时抑制 NREM 和 REM 睡眠 ^49,95–98 。这种睡眠变化与在细菌和锥虫感染中观察到的宿主免疫反应的过程相关 ^97,99 。支持性地，NREM睡眠的增加是兔子在传染病 ⁹⁶ 期间的有利预后因素。

Immune regulators also mediate the complex interrelation between sleep and the circadian systems⁷⁴. Circadian rhythms in behavior and physiology are generated by a molecular clockwork located in the suprachiasmatic nucleus, i.e., the master circadian pacemaker, and peripheral tissues, and involving the so-called clock genes (Clock, Bmals, Npas2, Crys, Pers, Rors, and Rev-erbs)¹⁰⁰. Cytokines, including TNF-α, IL-1β^101,102, and LPS^103–105, suppress the peripheral and hypothalamic expression of core clock genes and clock-controlled genes, resulting in reduced locomotor activity accompanied by prolonged rest time¹⁰¹.
免疫调节剂还介导睡眠和昼夜节律系统 ⁷⁴ 之间复杂的相互关系。行为和生理学中的昼夜节律是由位于视交叉上核（即主昼夜节律起搏器）和外周组织的分子发条产生的，并涉及所谓的时钟基因（Clock、Bmals、Npas2、Crys、Pers、Rors 和 Rev-erbs）。 ¹⁰⁰ 细胞因子，包括 TNF-α、IL-1β ^101,102 和 LPS ^103–105 ，抑制核心时钟基因和时钟控制基因的外周和下丘脑表达，导致运动活动减少，同时延长休息时间 ¹⁰¹ 。

Sleep deprivation and immune-related disease outcomes
睡眠剥夺和免疫相关疾病结局

In the following section, the association between sleep deprivation and risk or outcomes of immune-related disorders, as observed in human studies (mostly observational) and animal experimentations, will be examined. In this context, considering the sleep–immunity relationship, research has also begun to explore whether and how immune deregulation and inflammation may link sleep deprivation with adverse health outcomes.
在下一节中，将研究在人体研究（主要是观察性）和动物实验中观察到的睡眠剥夺与免疫相关疾病的风险或结果之间的关联。在这种情况下，考虑到睡眠-免疫关系，研究也开始探索免疫失调和炎症是否以及如何将睡眠剥夺与不良健康结果联系起来。

Immune mechanisms linking sleep deprivation and diseases
睡眠剥夺与疾病相关的免疫机制

As shown above, sleep deprivation has been found to alter inflammatory immune processes via multiple pathways, which could lead to increased susceptibility to chronic inflammatory diseases (Fig. 2). Most of the current knowledge on immune effects of sleep deprivation come from studies using controlled experimental sleep deprivation protocols, among which chronic partial sleep deprivation, lasting 2–15 days, is that mostly resembling the human condition of chronic insufficient sleep.
如上图所示，已发现睡眠剥夺通过多种途径改变炎症免疫过程，这可能导致对慢性炎症性疾病的易感性增加（图2）。目前关于睡眠剥夺的免疫影响的大多数知识来自使用受控实验性睡眠剥夺方案的研究，其中持续 2-15 天的慢性部分睡眠剥夺与人类长期睡眠不足的状况非常相似。

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Fig. 2 图2

Immune consequences of sleep deprivation.
睡眠剥夺的免疫后果。

Sleep deprivation, as induced experimentally or in the context of habitual short sleep, has been found to be associated with alterations in the circulating numbers and/or activity of total leukocytes and specific cell subsets, elevation of systemic and tissue (e.g., brain) pro-inflammatory markers including cytokines (e.g., interleukins [IL], tumor necrosis factor [TNF]-α), chemokines and acute phase proteins (such as C reactive Protein [CRP]), altered antigen presentation (reduced dendritic cells, altered pattern of activating cytokines, etc.), lowered Th1 response, higher Th2 response, and reduced antibody production. Furthermore, altered monocytes responsiveness to immunological challenges such as lipopolysaccharide (LPS) may contribute to sleep deprivation-associated immune modulation. Hypothesized links between immune dysregulation by sleep deprivation and the risk for immune-related diseases, such as infectious, cardiovascular, metabolic, and neurodegenerative and neoplastic diseases, are shown. The illustrations were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. APC: antigen-presenting cells.
已发现通过实验或习惯性短睡眠诱导的睡眠剥夺与总白细胞和特定细胞亚群的循环数量和/或活性的改变、全身和组织（例如大脑）促炎标志物（例如白细胞介素 [IL]、肿瘤坏死因子 [TNF]-α）、趋化因子和急性期蛋白（如 C 反应蛋白 [CRP]）的升高有关， 抗原呈递改变（树突状细胞减少、细胞因子激活模式改变等）、Th1 反应降低、Th2 反应升高和抗体产生减少。此外，单核细胞对脂多糖 （LPS） 等免疫挑战的反应改变可能有助于睡眠剥夺相关的免疫调节。显示了睡眠剥夺导致的免疫失调与免疫相关疾病（如传染病、心血管疾病、代谢疾病、神经退行性疾病和肿瘤性疾病）风险之间的假设联系。插图修改自 Servier Medical Art （ http://smart.servier.com/），根据 Creative Common Attribution 3.0 通用许可获得许可。APC：抗原呈递细胞。

Some studies have observed that sleep deprivation, compared with regular nocturnal sleep, leads to increased circulating numbers of total leukocytes and specific cell subsets mainly neutrophils, monocytes, B cells, CD4 T cells, and decreased circulating numbers and cytotoxic activity of NK cells^{203,210–213}. Other studies, however, found contrasting results, including a decrease in CD4 T cells after sleep deprivation^213,214, probably due to differences in sleep deprivation protocol, sampling methodologies, and other factors. Sleep deprivation has also shown to alter circadian rhythm of circulating leukocytes²¹⁵, with higher levels during the night and at awakening and a flattened rhythm^210,212. Additional findings are suggestive of immune deregulation by sleep deprivation, including a decreased neutrophils phagocytic activity²¹³, altered lymphocytes adhesion molecule expression²¹⁶, and reduced stimulated production of IL-2 and IL-12, which are important for adaptive immunity^211,217.
一些研究观察到，与正常的夜间睡眠相比，睡眠剥夺导致总白细胞和特定细胞亚群（主要是中性粒细胞、单核细胞、B 细胞、CD4 T 细胞）的循环数量增加，以及 NK 细胞 ^{203,210–213} 的循环数量和细胞毒性活性降低。然而，其他研究发现了截然不同的结果，包括睡眠剥夺后CD4 T细胞的减少 ^213,214 ，可能是由于睡眠剥夺协议，采样方法和其他因素的差异。睡眠剥夺也被证明会改变循环白细胞的昼夜节律 ²¹⁵ ，在夜间和醒来时水平较高，节律扁平 ^210,212 。其他发现提示睡眠剥夺导致的免疫失调，包括中性粒细胞吞噬活性 ²¹³ 降低、淋巴细胞粘附分子表达 ²¹⁶ 改变以及 IL-2 和 IL-12 的刺激产生减少，这对适应性免疫很重要 ^211,217 。

Experimental sleep deprivation has been reported to affect systemic markers of inflammation, with studies showing increased circulating pro-inflammatory molecules (IL-1, IL-6, CRP, TNF-α, and MCP-1); this associated in some studies with a subsequent homeostatic increase in endogenous inhibitors, including IL-1 receptor antagonist and TNF receptors^{203,218–220}. In agreement with experimental sleep deprivation, population studies found a direct independent association between habitual short sleep duration (generally < 5 or 6 h) and elevated circulating pro-inflammatory markers, e.g., acute phase proteins (CRP and IL-6), cytokines (TNF-α, IFN-γ, IL-1, etc.), adhesion molecules, and leukocyte counts^{183,221–225}. Furthermore, a reduced NK cell activity²²⁶ and a decline in naive T cells²²⁷, compatible with reduced immune competence, was reported in association with habitual short sleep. Shortening of leukocyte telomere length, a cellular senescence marker linked with inflammation, was also associated with shorter sleep duration^228,229.
据报道，实验性睡眠剥夺会影响炎症的全身标志物，研究表明循环促炎分子（IL-1、IL-6、CRP、TNF-α 和 MCP-1）增加;在一些研究中，这与随后内源性抑制剂（包括 IL-1 受体拮抗剂和 TNF 受体）的稳态增加有关 ^{203,218–220} 。与实验性睡眠剥夺一致，人群研究发现习惯性短睡眠时间（通常< 5 或 6 小时）与循环促炎标志物升高之间存在直接独立关联，例如急性期蛋白（CRP 和 IL-6）、细胞因子（TNF-α、IFN-γ、IL-1 等）、粘附分子和白细胞计数 ^{183,221–225} 。此外，据报道，NK细胞活性 ²²⁶ 降低和幼稚T细胞 ²²⁷ 下降，与免疫能力降低相符，与习惯性短睡眠有关。白细胞端粒长度的缩短是与炎症相关的细胞衰老标志物，也与较短的睡眠时间有关 ^228,229 。

The reported elevation of systemic inflammation is clinically relevant, because it is suggested to specifically mediate the increased risk of mortality associated with short sleep^23,230,231 and, as observed, the risk for chronic disease development.
报告的全身炎症升高具有临床意义，因为建议特异性介导与睡眠 ^23,230,231 不足相关的死亡风险增加，以及所观察到的慢性疾病发展风险。

Regarding cellular markers of inflammation, some studies found that the ex-vivo LPS-stimulated production of TNF-α^232,233, IL-1β, and IL-6^{203,232–234} by human monocytes increased during sleep deprivation but decreased during regular nocturnal sleep^{54,203,232–234}. However, other studies reported a decrease of TNF-α production by activated monocytes after sleep deprivation compared with regular nocturnal sleep^203,235. These contrasting results need further investigations and may depend on differences in the cytokine sensitivity to different sleep deprivation protocols or sampling methods and time. For instance, it seems that partial acute sleep deprivation increased stimulated monocytic TNF-α production^232,233, whereas more sustained sleep deprivation decreased it^203,235.
关于炎症的细胞标志物，一些研究发现，人单核细胞离体LPS刺激的TNF-α ^232,233 、IL-1β和IL-6 ^{203,232–234} 的产生在睡眠剥夺期间增加，但在正常夜间睡眠 ^{54,203,232–234} 期间减少。然而，其他研究报告称，与常规夜间睡眠 ^203,235 相比，睡眠剥夺后激活的单核细胞产生的 TNF-α 减少。这些对比结果需要进一步研究，并且可能取决于细胞因子对不同睡眠剥夺方案或采样方法和时间的敏感性的差异。例如，似乎部分急性睡眠剥夺增加了刺激的单核细胞TNF-α的产生，而更持久的睡眠剥夺则减少了单 ^203,235 核细胞TNF-的产生 ^232,233 。

Undisturbed sleep is predominantly characterized by a Th1 polarization of Th cells (expressing IFN-γ, IL-2, and TNF-α), and experimental sleep deprivation in humans leads to a shift from a Th1 pattern towards a Th2 pattern (expressing IL-4, IL-5, IL-10, and IL-13)^217,236. Accordingly, conditions featured by disturbed sleep with specific deficit in slow wave sleep, as observed in elderly people²³⁷, alcoholic²³⁸, and insomnia²³⁹ patients, show a cytokine shift towards Th2. The balance of Th1/Th2 immunity and its shift during sleep deprivation may have crucial implications in anti-microbial and anti-tumor immune responses. Th2 over-activity is known to be involved in some forms of allergic responses, and to increase the susceptibility to infection²⁴⁰. Likewise, regarding the anti-tumor immune action, Th1 response supports cytotoxic lymphocytes and tumor cells destruction with the potential of elimination or control of tumor cell growth, so that a type 1 adaptive immune response (increased antigen presentation, IFN-γ signaling, and T-cell receptor signaling) may be associated with an improved survival or prognosis^241,242. In contrast, Th2 over-response is thought to contribute to tumor development and progression, by limiting cytotoxic T lymphocytes proliferation and by the modulation of other inflammatory cell types²⁴¹.
不受干扰的睡眠主要特征是 Th 细胞的 Th1 极化（表达 IFN-γ、IL-2 和 TNF-α），人类的实验性睡眠剥夺导致从 Th1 模式转变为 Th2 模式（表达 IL-4、IL-5、IL-10 和 IL-13）。 ^217,236 因此，在老年人 ²³⁷ 、酗酒 ²³⁸ 者和失眠 ²³⁹ 患者中观察到的以慢波睡眠中特定缺陷的睡眠障碍为特征的病症显示细胞因子向 Th2 转移。Th1/Th2免疫的平衡及其在睡眠剥夺期间的转变可能对抗菌和抗肿瘤免疫反应具有至关重要的意义。已知 Th2 过度活动与某些形式的过敏反应有关，并增加对感染 ²⁴⁰ 的易感性。同样，关于抗肿瘤免疫作用，Th1 反应支持细胞毒性淋巴细胞和肿瘤细胞破坏，具有消除或控制肿瘤细胞生长的潜力，因此 1 型适应性免疫反应（增加抗原呈递、IFN-γ 信号传导和 T 细胞受体信号传导）可能与生存或 ^241,242 预后改善有关.相比之下，Th2 过度反应被认为通过限制细胞毒性 T 淋巴细胞增殖和调节其他炎症细胞类型 ²⁴¹ 来促进肿瘤的发展和进展。

Several cellular and molecular signaling pathways may be involved in mediating the influence of sleep deprivation on immune and inflammatory functions (Fig. 3). Increased oxidative stress markers and/or decreased antioxidant defense have been found after sleep deprivation^243–245. Sleep shows an antioxidant function, responsible for eliminating reactive oxygen species produced during wakefulness, and contrarily sleep deprivation may cause oxidative stress, which leads to cell senescence, unbalanced local/systemic inflammation, dysmetabolism, and immune derangements^246,247.
几种细胞和分子信号通路可能参与介导睡眠剥夺对免疫和炎症功能的影响（图3）。睡眠剥夺后发现氧化应激标志物增加和/或抗氧化防御能力下降 ^243–245 。睡眠具有抗氧化功能，负责消除清醒时产生的活性氧，相反，睡眠不足可能会导致氧化应激，从而导致细胞衰老、局部/全身炎症失衡、代谢紊乱和免疫紊乱 ^246,247 。

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Fig. 3 图3

Pro-inflammatory molecular pathways induced by sleep deprivation.
睡眠剥夺诱导的促炎分子通路。

A schematic model of potential mechanistic pathways linking sleep deprivation and inflammatory immune activation is depicted. Sleep deprivation is associated with activation of the sympathetic nervous system and release of norepinephrine and epinephrine into the systemic circulation, as well as to some extent with impaired hypothalamus-pituitary axis stimulation. These neuromediators may act along with other potential stimuli accumulated following sleep deprivation including reactive oxygen species (ROS), adenosine, metabolic waste products (e.g., β-amyloid) not cleared during normal sleep, gut microbiota dysbiosis leading to altered local and systemic pattern of metabolic products, as well as with changes in the profile of neuro-endocrine hormones, such as prolactin, growth hormone, and altered circadian rhythm of melatonin secretion. In immune cells located in the brain and the peripheral tissues, these stimuli may in concert trigger inflammatory activation, with release of cytokines, chemokines, acute phase protein, etc. via the recruitment of transcriptional regulators of pro-inflammatory gene expression, mainly nuclear factor (NF)-κB, and disturbing the circadian rhythmicity of gene expression of both clock genes and metabolic, immune and stress response genes (see text for further detail). E: epinephrine; NE: norepinephrine; TLR: Toll-like receptor. Arrows indicate stimulation; lines indicate inhibition. The illustrations were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.
描述了将睡眠剥夺和炎症免疫激活联系起来的潜在机制通路的示意图模型。睡眠剥夺与交感神经系统的激活和去甲肾上腺素和肾上腺素释放到体循环中有关，并且在某种程度上与下丘脑 - 垂体轴刺激受损有关。这些神经介质可能与睡眠剥夺后积累的其他潜在刺激一起起作用，包括活性氧 （ROS）、腺苷、正常睡眠期间未清除的代谢废物（例如β-淀粉样蛋白）、肠道菌群失调导致代谢产物的局部和全身模式改变，以及神经内分泌激素（如催乳素）谱的变化， 生长激素和褪黑激素分泌的昼夜节律改变。在位于大脑和外周组织的免疫细胞中，这些刺激可能协同触发炎症激活，通过募集促炎基因表达的转录调节因子（主要是核因子 （NF）-κB）释放细胞因子、趋化因子、急性期蛋白等，并扰乱时钟基因和代谢基因表达的昼夜节律性， 免疫和应激反应基因（详见正文）。E：肾上腺素;NE：去甲肾上腺素;TLR：Toll样受体。箭头表示刺激;线条表示抑制。插图修改自 Servier Medical Art （ http://smart.servier.com/），根据 Creative Common Attribution 3.0 通用许可获得许可。

Effects of sleep deprivation on the immune response may derive from the activation of the SNS with the corresponding increase in systemic catecholamines^22,248. Catecholamines signal to immune cells via adrenergic receptors, which are primarily α- and β-adrenergic in myeloid cells and β-adrenergic in lymphocytes²⁴⁹. The immune outcome of the sympathetic signaling is complex, and includes both stimulatory and inhibitory effects depending on cell and receptor types, cell development/activation states, and local microenvironment^249,250. Some evidence suggest that β-adrenergic signaling inhibits and α-adrenergic signaling promotes excessive inflammation under endotoxemia²⁵⁰. Activation of α-adrenergic signaling in peripheral tissues induces the upregulation of pro-inflammatory cytokines^250,251. Sympathetic activation also suppresses the transcription of type I IFNs (IFN-α and IFN-β) genes and interferon response genes, which play a key role in anti-viral immunity²⁵², and inhibits via β-adrenergic signaling the anti-tumor cytotoxicity of T lymphocytes²⁵³. In vitro β-adrenergic stimulation repressed Th1 response and stimulated Th2 response, with varying effects found in vivo^249,254. Although the specific role of SNS activation in the immune phenotype associated with sleep deprivation is not clearly established, data suggest a pro-inflammatory effect of SNS under sleep deprivation. Indeed, chemical sympathectomy has been recently shown to alleviate the inflammatory response following chronic sleep deprivation in mice²⁵⁵, and both α- and, to a lesser extent, β-adrenergic receptors seem to contribute to the sympathetic regulation of inflammatory responses to sleep deprivation²⁵⁶.
睡眠剥夺对免疫反应的影响可能源于SNS的激活以及全身儿茶酚胺的相应增加 ^22,248 。儿茶酚胺通过肾上腺素能受体向免疫细胞发出信号，肾上腺素能受体在髓系细胞中主要是α肾上腺素能和β肾上腺素能，在淋巴细胞中是β肾上腺素能 ²⁴⁹ 。交感神经信号转导的免疫结果是复杂的，包括刺激和抑制作用，具体取决于细胞和受体类型、细胞发育/激活状态和局部微环境 ^249,250 。一些证据表明，β-肾上腺素能信号传导抑制和α-肾上腺素能信号传导促进内毒素血症下的过度炎症 ²⁵⁰ 。外周组织中α肾上腺素能信号传导的激活诱导促炎细胞因子的上调 ^250,251 。交感神经激活还抑制I型IFN（IFN-α和IFN-β）基因和干扰素反应基因的转录，这些基因在抗病毒免疫中起关键作用 ²⁵² ，并通过β-肾上腺素能信号抑制T淋巴细胞的抗肿瘤细胞毒性 ²⁵³ 。体外β肾上腺素能刺激抑制Th1反应并刺激Th2反应，在体内发现不同的效果 ^249,254 。尽管SNS激活在与睡眠剥夺相关的免疫表型中的具体作用尚不清楚，但数据表明SNS在睡眠剥夺下具有促炎作用。事实上，化学交感神经切除术最近已被证明可以减轻小鼠慢性睡眠剥夺后的炎症反应 ²⁵⁵ ，并且α和在较小程度上β肾上腺素能受体似乎都有助于对睡眠剥夺的炎症反应的交感神经调节 ²⁵⁶ 。

At the molecular levels, sleep deprivation led to significant gene expression changes in animal tissues^257–259 and human blood monocytes^{203,233,260–262}, with affected genes mostly related to immune and inflammatory processes (leukocyte function, Th1/Th2 balance, cytokine regulation, and TLR signaling), oxidative stress, stress response, apoptosis, and circadian system, collectively indicating immune activation and hyperinflammation.
在分子水平上，睡眠剥夺导致动物组织 ^257–259 和人血液单核细胞的基因表达发生显著变化 ^{203,233,260–262} ，受影响的基因主要与免疫和炎症过程（白细胞功能、Th1/Th2平衡、细胞因子调节和TLR信号传导）、氧化应激、应激反应、细胞凋亡和昼夜节律系统有关，共同表明免疫激活和过度炎症。

Sleep loss and mistimed sleep also led in the blood transcriptome to alteration and reduction in the circadian rhythmicity of gene expression^261,263, which is an integral part of basic biological processes and homeostasis^264–266.
睡眠不足和不合时宜的睡眠也导致血液转录组改变和降低基因表达 ^261,263 的昼夜节律性，这是基本生物过程和稳态的一个组成部分 ^264–266 。

The activation of the pro-inflammatory NF-κB/Rel family of transcription factors by sleep deprivation, first demonstrated in the late 1990s in mice²⁶⁷, and subsequently widely confirmed^{233,260,261,268–272}, is one of the most consistent findings regarding upstream transcriptional regulation. NF-κB induces the expression of genes (e.g., cytokines/chemokines, growth factors, receptors/transporters, enzymes, adhesion molecules) involved in inflammation, immunity, proliferation, and apoptosis²⁷³, circadian clock activity²⁷⁴, and sleep propensity²⁷⁵. Potential signals for NF-κB activation under sleep deprivation include increased adenosine levels, oxidative stress, altered metabolism (adiposity and decreased insulin sensitivity), brain proteins/metabolites (e.g., Aβ), melatonin suppression²⁷⁶, circadian clock proteins²⁷⁷, and catecholamine surge due to increased sympathetic activity²⁷⁸. Given the role of NF-κB in the pathophysiology of inflammatory diseases²⁷³, its activation under sleep deprivation may be a common pathway for the risk of morbidity and mortality.
1990年代后期，在小鼠中首次发现，通过睡眠剥夺激活促炎性NF-κB/Rel转录因子家族 ²⁶⁷ ，随后被广泛证实 ^{233,260,261,268–272} ，这是关于上游转录调控的最一致的发现之一。NF-κB 诱导参与炎症、免疫、增殖和凋亡 ²⁷³ 、生物钟活动 ²⁷⁴ 和睡眠倾向的基因（例如细胞因子/趋化因子、生长因子、受体/转运蛋白、酶、粘附分子 ²⁷⁵ ）的表达。睡眠剥夺下NF-κB激活的潜在信号包括腺苷水平升高、氧化应激、代谢改变（肥胖和胰岛素敏感性降低）、脑蛋白/代谢物（例如Aβ）、褪黑激素抑制 ²⁷⁶ 、生物钟蛋白 ²⁷⁷ 和儿茶酚胺激增由于交感神经活动 ²⁷⁸ 增加。鉴于NF-κB在炎症性疾病 ²⁷³ 的病理生理学中的作用，它在睡眠剥夺下的激活可能是发病和死亡风险的常见途径。

The intestinal microbiota is also affected by sleep loss^279–281, showing indices of dysbiosis (increased Firmicutes:Bacteroidetes ratio; decreased diversity and richness), which may affect the immune system²⁸², and are similar to those associated with cardiometabolic diseases⁴⁵.
肠道微生物群也受到睡眠不足 ^279–281 的影响，显示出生态失调的指数（厚壁菌门：拟杆菌门比率增加;多样性和丰富度降低），这可能影响免疫系统 ²⁸² ，并且与心脏代谢疾病 ⁴⁵ 相关。

Countermeasures for sleep deprivation: effect on immune parameters
睡眠剥夺的对策：对免疫参数的影响

Although the impact of strategies to improve sleep duration on neurobehavioral performance and alertness after sleep deprivation have been assessed^283–285, sleep deprivation countermeasures to improve immune and inflammatory parameters, and, correspondingly, disease risk and outcomes have been studied to a lesser extent.
尽管已经评估 ^283–285 了改善睡眠持续时间的策略对睡眠剥夺后神经行为表现和警觉性的影响，但改善免疫和炎症参数的睡眠剥夺对策，以及相应的疾病风险和结果的研究程度较小。

Although extension of habitual short sleep did not show to significantly counterbalance the immune consequence of sleep deprivation^286–288, mixed results derive from nighttime recovery sleep following sleep deprivation (Table 1), with limited evidence of effectiveness for specific immune parameters^210,214, and mostly after multiple consecutive nights of 8 h sleep recovery or with an extended nocturnal sleep duration^212,289.
虽然习惯性短睡眠的延长并没有显示出显著抵消睡眠剥夺的免疫后果 ^286–288 ，但睡眠剥夺后的夜间恢复睡眠得出了不同的结果（表1），对特定免疫参数 ^210,214 的有效性证据有限，而且大多是在连续多个晚上8小时睡眠恢复或夜间睡眠持续时间延长 ^212,289 之后。

Although daytime napping (<20 min) restores alertness, and mental and physical performance without provoking sleep inertia associated with longer nap^290–292, the effects of a short nap on immune/inflammatory parameters after sleep deprivation have yet to be firmly established. Differently form population studies²⁹³, laboratory studies found immune benefit from nap^{218,289,294,295}. Regarding immune-related clinical outcomes, controversy exists, with studies finding no association²⁹⁶, inverse associations^297,298 or positive association²⁹⁶, and a J-shaped relationship^299–301 between napping and CV and metabolic diseases or cancer events and mortality. Whether changes in immune parameters could contribute to the associations between napping and immune-related diseases remains unclear.
虽然白天小睡（<20分钟）可以恢复警觉性，并在不引起与较长午睡相关的睡眠惯性的情况下恢复精神和身体表现 ^290–292 ，但短睡对睡眠剥夺后免疫/炎症参数的影响尚未确定。与不同形式的人群研究 ²⁹³ ，实验室研究发现午睡对免疫有益 ^{218,289,294,295} 。关于免疫相关的临床结果，存在争议，研究发现没有关联 ²⁹⁶ 、负相关 ^297,298 或正相关 ²⁹⁶ ，午睡与心血管与代谢疾病或癌症事件和死亡率之间存在 J 型关系 ^299–301 。免疫参数的变化是否有助于午睡与免疫相关疾病之间的关联尚不清楚。

Among the strategies to recover sleep deprivation-induced immune changes, cognitive behavior therapy improves sleep outcomes in insomnia and lowers cellular and systemic inflammatory markers^302,303, and the risk score composed of CV and metabolic risk factors³⁰⁴. This highlights the potential role of targeting sleep in reducing the inflammatory risk and the associated chronic diseases.
在恢复睡眠剥夺诱导的免疫变化的策略中，认知行为疗法改善了失眠患者的睡眠结果，降低了细胞和全身炎症标志物 ^302,303 ，以及由CV和代谢危险因素 ³⁰⁴ 组成的风险评分。这凸显了以睡眠为目标在降低炎症风险和相关慢性疾病方面的潜在作用。

Summary and concluding remarks
总结和结束语

Sleep exerts immune-supportive functions and impairments of the immune-inflammatory system are a plausible mechanism mediating the negative health effects of sleep deprivation, and in particular, its role in the risk and outcomes of chronic diseases such as infections, CV, metabolic and autoimmune diseases, NDDs, and cancer. Caution should be exercised in interpreting cellular and molecular outcomes of sleep deprivation in experimental studies conducted till now as a result of an independent effect of sleep deprivation, because other factors may play a role, including extended wakefulness-associated processes, other features of sleep-wakefulness, their temporal and functional segregation or methodologies of sleep manipulation.
睡眠发挥免疫支持功能，免疫炎症系统的损伤是一种合理的机制，介导睡眠剥夺对健康的负面影响，特别是它在慢性疾病（如感染、心血管、代谢和自身免疫性疾病、NDD 和癌症）的风险和结果中的作用。在迄今为止进行的实验研究中，由于睡眠剥夺的独立影响，在解释睡眠剥夺的细胞和分子结果时应谨慎，因为其他因素可能起作用，包括延长的觉醒相关过程、睡眠觉醒的其他特征、它们的时间和功能分离或睡眠操纵方法。

Randomized controlled trials assessing the effect of treatment of sleep deprivation on inflammatory immune dysfunction and/or health outcomes are needed. Knowledge of inflammatory and immunological signatures in response to sleep curtailment may inform not only on the underlying molecular links, but also contribute to refine risk profiles to be used for developing biomarkers of sleep deprivation and sleep disturbance-related health outcomes, which may also represent potential targets of interventions. Recent metabolomic³⁰⁵ and transcriptomic³⁰⁶ studies hold promise in biomarker discovery³⁰⁶.
需要随机对照试验来评估睡眠剥夺治疗对炎症性免疫功能障碍和/或健康结局的影响。对睡眠减少反应的炎症和免疫特征的了解不仅可以为潜在的分子联系提供信息，还有助于完善风险概况，用于开发睡眠剥夺和睡眠障碍相关健康结果的生物标志物，这也可能代表潜在的干预目标。最近的代谢组学 ³⁰⁵ 和转录组 ³⁰⁶ 学研究在生物标志物发现 ³⁰⁶ 方面很有希望。

These efforts may converge towards a new ground fostering interactions between the sleep research and the medical community to translate scientific knowledge into the clinic, prioritize health issues, and develop strategies and policies for subject risk stratification, to include evidence-based sleep recommendations in guidelines for optimal health and to address sleep hygiene at the individual and the population levels, as a means to prevent the negative health consequences of sleep deprivation. These actions might also foster health literacy and empowerment of individuals to actively better manage their own health and well-being throughout their life course by means of lifestyle, nutritional, and behavioral habits including sleep hygiene³⁰⁷.
这些努力可能会汇聚到一个新的领域，促进睡眠研究和医学界之间的互动，将科学知识转化为临床，优先考虑健康问题，并制定受试者风险分层的战略和政策，将循证睡眠建议纳入最佳健康指南，并解决个人和人群层面的睡眠卫生问题， 作为防止睡眠不足对健康造成负面影响的一种手段。这些行动还可以通过生活方式、营养和行为习惯（包括睡眠卫生）来促进个人的健康素养和赋权，从而在整个生命过程中积极更好地管理自己的健康和福祉 ³⁰⁷ 。

Conclusively, in the perspective of staying healthy in this rapidly changing society, the sleep–immunity relationship raises relevant clinical implications for promoting sleep health and, as evidenced here, for improving or therapeutically controlling inflammatory response by targeting sleep. This may ultimately translate, in the era of preventive medicine, into addressing sleep as a lifestyle approach along with diet and physical activity to benefit overall public health.
总而言之，从在这个瞬息万变的社会中保持健康的角度来看，睡眠-免疫关系对促进睡眠健康提出了相关的临床意义，正如本文所证明的那样，通过针对睡眠来改善或治疗控制炎症反应。在预防医学时代，这可能最终转化为将睡眠作为一种生活方式，以及饮食和身体活动，以造福整体公共卫生。

Supplementary information
补充资料

Author contributions 作者贡献

E.S. reviewed the literature and wrote the manuscript draft. S.G. and P.L. contributed to writing the manuscript and revised the manuscript draft. N.L.B. and N.M. reviewed the final manuscript.
E.S.审阅了文献并撰写了手稿。S.G. 和 P.L. 参与了手稿的撰写，并修改了手稿草稿。N.L.B. 和 N.M. 审阅了最终手稿。

Data availability 数据可用性

All data generated or analysed during this study are included in this published article.
本研究期间生成或分析的所有数据都包含在这篇已发表的文章中。

Competing interests 利益争夺

The authors declare no competing interests.
作者声明没有竞争利益。

Footnotes 脚注

References 引用