温故而知新专栏 | 译作分享：炎症，与压力有关的疾病的共同途径（上）

文摘健康 2024-10-23 17:03 北京

译作分享

Inflammation: The Common Pathway of Stress-Related Diseases

炎症：与压力有关的疾病的共同途径

Yun-Zi Liu, Yun-Xia Wang and Chun-Lei Jiang*

Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, Shanghai, China

刘云子，王云霞和蒋春雷

中国上海第二军医大学心理与精神卫生学院应激医学实验室

While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%–90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases.

现代化在极大地延长寿命的同时，也见证了压力的本质发生了巨大的变化。慢性压力导致体内平衡失调，从而导致各种疾病，如动脉粥样硬化、非酒精性脂肪性肝病(NAFLD)和抑郁症。然而，虽然75%-90%的人类疾病与压力系统的激活有关，但应激暴露与疾病病理生理过程的共同途径仍存在争议。慢性炎症是慢性疾病的重要组成部分。此外，越来越多的证据表明，过度炎症在压力相关疾病的病理生理学中发挥着关键作用，但这种联系的基础尚未完全破解。在此，我们讨论了炎症在压力性疾病中的作用，并提出了一种基于慢性轻度炎症的压力相关疾病的共同途径。这个框架强调了炎症机制的基本影响，并为压力相关疾病的预防和治疗提供了一个新的视角。

Introduction/介绍

Stress is a state of threatened homeostasis provoked by a psychological, environmental, or physiological stressor. With rapid development of science and technology, as well as economy and strong social competition, the nature of stress has changed dramatically (Landsbergis, 2003). Stressful events engender multiple neurochemical, neurotransmitter and hormonal alterations by mainly activating the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. When stress stimuli are under control, the body responds to these in the physiological way. SNA and HPA axis are woken up to release chemical mediators to protect our body from stress. For instance, catecholamines are elevated to increase heart rate and blood pressure, which help us to fight or flight. This appropriate body reaction was called “allostasis” by Sterling and Eyer (1988). This state is beneficial to our survival and recovery. However, when stress stimuli are prolonged or over exaggerated, in another word, chronically increased allostasis lead to pathophysiology. In the last two decades, accumulating evidence indicated that severe or prolonged (chronic) stress resulted in increased risk for physical and psychiatric disorders, which is called stress-related disease. Stress is the common risk factor of 75%–90% diseases, including the diseases which cause the foremost morbidity and mortality. According to the former review, the most common stress-related diseases are cardiovascular diseases (CVD, i.e., hypertension and atherosclerosis), metabolic diseases (i.e., diabetes and non-alcoholic fatty liver disease, NAFLD), psychotic and neurodegenerative disorders (i.e., depression, Alzheimer’s disease, AD and Parkinson’s disease, PD), cancer (Cohen et al., 2007).

压力是一种由心理、环境或生理压力源引起的内稳态受到威胁的状态。随着科学技术的快速发展，以及经济和社会竞争的激烈，压力的性质发生了巨大的变化(Landsbergis, 2003)。压力事件主要通过激活交感神经系统(SNS)和下丘脑-垂体-肾上腺(HPA)轴，产生多种神经化学、神经递质和激素改变。当压力刺激受到控制时，身体会以生理方式对其做出反应。SNA和HPA轴被唤醒，释放化学介质来保护我们的身体免受压力。例如，儿茶酚胺升高会增加心率和血压，这有助于我们战斗或逃跑。这种适当的身体反应被Sterling和yer(1988)称为“异稳态”。这种状态有利于我们的生存和恢复。然而，当压力刺激被延长或过度夸大时，换句话说，长期增加的异稳态导致病理生理。在过去二十年中，不断积累的证据表明，严重或长期（慢性）压力导致身体和精神障碍的风险增加，这被称为与压力有关的疾病。压力是75%-90%疾病的共同危险因素，包括导致发病率和死亡率最高的疾病。根据之前的回顾，最常见的与压力相关的疾病是心血管疾病(CVD，即高血压和动脉粥样硬化)、代谢性疾病(即糖尿病和非酒精性脂肪性肝病，NAFLD)、精神疾病和神经退行性疾病(即抑郁症、阿尔茨海默病、AD和帕金森病，PD)、癌症(Cohen et al.， 2007)。

The traditional standpoint of mechanisms linking stress and disease has focused on the classical stress systems—the HPA axis and SNS. However, alterations in HPA axis and SNS mainly have indirect effects on target systems; thus the mechanisms link stress to stress-related diseases, and are still under debate. Recently, inflammation as a new and promising biological mechanism is proposed (Rohleder, 2014). Accumulating literatures showed that excessive inflammation directly contribute to pathophysiology of stress-related diseases. In this review article, the search terms were combinations of the following (literatures were selected from PubMed): stress (“social stress” or “psychosocial stress” or “psychophysiological stress” or “mental stress”), disease (“CVD” or “metabolic diseases” or “psychotic and neurodegenerative disorders” or “cancer”), and inflammation (“Inflammatory” or “cytokines”). We make a brief summary of stress and inflammation in the field of stress-related diseases. On the basis of these reports, we further hypothesize that inflammation may be one of the common pathways of stress-related diseases.

传统的观点认为压力和疾病之间的联系主要集中在经典的压力系统——HPA轴和SNS。而HPA轴和SNS的改变对目标系统的影响主要是间接的; 因此，将压力和与压力相关的疾病联系起来的机制仍在争论之中。最近，有人提出炎症是一种新的、且有潜力的生物机制(Rohleder, 2014)。越来越多的文献表明，过度的炎症直接促进了压力相关疾病的病理生理。在这篇综述文章中，检索词是以下组合(文献选自PubMed)：压力 (“社会压力”或“社会心理压力”或“心理生理压力”或“精神压力”)，疾病 (“CVD”或“代谢性疾病”或“精神病和神经退行性疾病”或“癌症”)，以及炎症 (“炎症”或“细胞因子”)。本文就压力相关疾病领域内的压力和炎症做了一个简单的总结。在这些报告的基础上，我们进一步假设，炎症可能是压力相关疾病的共同途径之一。

Large bodies of evidence indicate that stress can activate inflammatory response in brain as well as peripherally (Rohleder, 2014;Calcia et al., 2016).

大量证据表明，压力可以激活大脑及周边的炎症反应 (Rohleder, 2014; Calcia et al., 2016)。

There exists communication between the neuroendocrine and immune systems (Jiang et al., 1998；Quan and Banks, 2007). Stress activates the HPA axis through the hypothalamic secretion of corticotropin-releasing hormone (CRH), which normally suppresses immune responses through the release of glucocorticoids (GCs) from the adrenals. GCs are one of the major stress hormones released during stress response that are well known for their immunosuppressive and anti-inflammatory properties. Studies during the 1970s and 1980s revealed that GCs inhibited lymphocyte proliferation and cytotoxicity. Further, GCs reduce the expression of several pro-inflammatory cytokines (e.g., tumor necrosis factor α (TNF-α), interleukin-6 (IL-6)) and enhance the expression of anti-inflammatory cytokines (e.g., IL-10, TNF-β; Sorrells et al., 2009). However, recent researchers have proved that GCs also have pro-inflammatory impact on immune system (Elenkov, 2008). Rats with higher basal plasma corticosterone levels have more accumulation of PGE₂ whereas showing less anti-inflammatory factors after acute stress (Pérez-Nievas et al., 2007). GCs enhance the expression and function of inflammasome NLRP3, promoting the secretion of IL-1β in response to ATP. Inflammasomes are cytoplasmic multi-protein complexes that sense exogenous and endogenous danger signals and cleave pro-inflammatory cytokines into mature cytokines such as IL-1β and IL-18. This work demonstrates the proinflammatory role for GCs, enhancing the activation of the innate immune system in response to danger signals (Busillo et al., 2011). Circulating pro-inflammatory factors such as IL-1, IL-6 and TNFα directly stimulate the pituitary-adrenal axis, resulting in increased serum levels of adrenocorticotropic hormone (ACTH) and GCs, which in turn inhibit the production of these pro-inflammatory factors (Alley et al., 2006; Danese et al., 2007； Steptoe et al., 2007； Miller et al., 2008). The interaction of immune system and HPA axis form the endocrine negative feedback loops. However, when cytokine is over-stimulated in some diseases, these negative feedback loops could be weakened by reduced cytoplasmic GC-receptor (GR) level and decreased expression of GR driven anti-inflammatory genes, thus leading to GC low-responsiveness (Sterling and Eyer, 1988). Besides GCs, the SNS and its main neurotransmitter, norepinephrine (NE) and neuropeptide Y (NPY), could regulate the immune and inflammatory function. NE promoted the secretion of inflammatory factors by increasing the phosphorylation of mitogen-activated protein kinases (MAPKs) through an α receptor-dependent pathway and NPY could elicit transforming growth factor-β (TGF-β) and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (Bellinger et al., 2008; Zhou et al., 2008; Huang et al., 2012).

神经内分泌和免疫系统之间存在互相联系(Jiang et al., 1998; Quan and Banks, 2007)。压力刺激下丘脑分泌促肾上腺皮质激素释放激素（CRH）激活HPA轴，CRH通常通过从肾上腺释放糖皮质激素（GCs）来抑制免疫反应。GCs是应激反应期间释放的主要应激激素之一，以其免疫抑制和抗炎特性而闻名。1970年代和1980年代的研究表明，GCs抑制淋巴细胞增殖和细胞毒性。此外，GC降低几种促炎细胞因子（例如，肿瘤坏死因子α（TNF-α），白细胞介素-6（IL-6））的表达，并增强抗炎细胞因子（例如IL-10，TNF-β）的表达 (Sorrells et al., 2009)。然而，最近的研究人员已经证明，GCs对免疫系统也有促炎作用(Elenkov, 2008)。基础血浆皮质酮水平较高的大鼠具有更多PGE2的堆积，而在急性应激后显示出较少的抗炎因子 (Pérez-Nievas et al., 2007)。GCs增强炎症体NLRP3的表达和功能，促进IL-1β响应ATP的分泌。炎症体是细胞质多蛋白复合物，可感知外源性和内源性危险信号，并将促炎细胞因子裂解为成熟的细胞因子，如IL-1β和IL-18。这项工作证明了GCs的促炎作用，增强了先天免疫系统对危险信号的激活(Busillo et al., 2011)。循环中的促炎因子如IL-1，IL-6和TNFα直接刺激垂体 - 肾上腺轴，导致血清中促肾上腺皮质激素（ACTH）和GCs的水平升高，这反过来又抑制了这些促炎因子的产生 (Alley et al., 2006; Danese et al., 2007; Steptoe et al., 2007; Miller et al., 2008)）。免疫系统和HPA轴的相互作用形成内分泌负反馈回路。然而，当细胞因子在某些疾病中被过度刺激时，这些负反馈回路可能会因细胞质GC受体（GR）水平降低和GR驱动的抗炎基因表达减少而被削弱，从而导致GCs的低反应性 (Sterling and Eyer, 1988)。除GCs外，SNS及其主要的神经递质，去甲肾上腺素（NE）和神经肽Y（NPY），可以调节免疫和炎症功能。NE通过α受体依赖的途径增加有丝分裂原活化蛋白激酶（MAPKs）的磷酸化来促进炎症因子的分泌，NPY可以通过Y1受体在巨噬细胞样细胞系RAW264.7中引发转化生长因子β（TGF-β）和TNFα产生 (Alley et al., 2006; Danese et al., 2007; Steptoe et al., 2007; Miller et al., 2008)）。

Both pro-inflammatory and anti-inflammatory mechanisms depend on the type and intensity of stressors. Acute stressors seem to enhance immune function, whereas chronic stressors are suppressive. Intense stressors over-activate the immune system, leading to the imbalance of inflammation and anti-inflammation. Reports from different labs have confirmed pro-inflammation induced by stress, including C-reactive protein (CRP), IL-6, TNFα, IL-1β and the transcription factor of “nuclear factor kappa B (NF-κB)” (Miller et al., 2009).

促炎和抗炎机制都取决于压力源的类型和强度。急性压力源似乎可以增强免疫功能，而慢性压力源是抑制性的。强烈的压力源会过度激活免疫系统，导致炎症和抗炎失衡。来自不同实验室的报告证实了由压力诱发的促炎症，包括C-反应蛋白（CRP），IL-6，TNFα，IL-1β和“核因子kappa B（NF-κB）”的转录因子(Miller et al., 2009)。

In addition to peripheral inflammation, central inflammation namely neuroinflammation, has also been found in stress condition (García-Bueno et al., 2008; Munhoz et al., 2008). Elevated pro-inflammatory cytokines, increased microglia activation and accumulation of peripherally-derived monocytes and macrophages were detected in the brain with psychological stress exposure (Johnson et al., 2005). As the brain-resident macrophages, microglia was considered to be the major pro-inflammatory cytokine source. Stress-elicited potentiate microglial activation is via both direct and indirect mechanisms. Microglia express both GC and mineralocorticoid receptors, thus microglia are likely to have direct response to corticosterone peak (Calcia et al., 2016). In addition, GC receptors also are highly present in the hippocampus and prefrontal cortex, so stress-induced corticosterone may have indirect effects on microglia. Besides this, a recent research display that CNS innate immune system can respond to an acute stressor, thereby releasing the danger signal high mobility group box-1 (HMGB-1) in the brain to prime microglia by acting on the NLRP3 inflammasome, in preparation for IL-1β secretion (Weber et al., 2015). Activated microglia display hypertrophic branch morphology with an enlarged soma and produce an exaggerated cytokine to recruit peripheral monocytes. Increased brain macrophages and circulating monocytes, contribute to elevated levels of pro-inflammatory cytokine production (i.e., IL-1β, TNFα, IL-6) in the brain (Wohleb and Delpech, 2016).

除了外周炎症外，在压力条件下也发现了中枢炎症，即神经炎症(García-Bueno et al., 2008; Munhoz et al., 2008)。暴露在心理压力下，大脑中检测到促炎细胞因子升高，小胶质细胞活化增加，以及外周来源的单核细胞和巨噬细胞的堆积(Johnson et al., 2005)。作为脑部驻留的巨噬细胞，小胶质细胞被认为是主要的促炎细胞因子来源。压力诱发的小胶质细胞是通过直接和间接机制进行激活的。小胶质细胞同时表达GC和盐皮质激素受体，因此小胶质细胞可能对皮质酮峰值有直接反应 (Calcia et al., 2016)。此外，GC受体也高度存在于海马体和前额叶皮层中，因此压力诱导的皮质酮可能对小胶质细胞产生间接影响。除此之外，最近的一项研究表明，中枢神经系统的先天免疫系统可以对急性应激源做出反应，从而在大脑中释放危险信号高迁移性组box-1（HMGB-1），通过作用于NLRP3炎症体来刺激小胶质细胞，为IL-1β分泌做准备 (Weber et al., 2015)。被激活的小胶质细胞显示出肥厚的分支形态，伴有增大的体细胞，并产生夸张的细胞因子以募集外周单核细胞。大脑巨噬细胞和循环单核细胞的增加有助于大脑中促炎细胞因子产生（即IL-1β，TNFα，IL-6）水平升高(Wohleb and Delpech, 2016)。

In common, over-activated immune system, increased activity through SNS pathways, and reduced GCs responsiveness may work tandemly in the activation of inflammatory responses during stress. GCs, catecholamines, cytokines and other mediators released by stress are thought to be the main mediators in stress-induced pro-inflammatory effect.

通常，过度激活的免疫系统，通过SNS途径增加的活动以及GCs反应性降低可能在压力期间协同激活炎症反应。GCs，儿茶酚胺，细胞因子和应激释放的其他介质被认为是压力诱导的促炎效应的主要介质。

Inflammation and Diseases

炎症和疾病

Classically, inflammation is classically known as the crucial response to microbe invasion or tissue injury to keep maintenance of tissue homeostasis. In recent years, our knowledge of the inflammation role is greatly enlarged. Inflammatory pathway has been recognized as a pivotal molecular basis in the pathogenesis of many chronic diseases. By far, increasing literatures have shown that excessive inflammation play critical roles in the progression, and/or onset of stress-related diseases. There has been a growing number of evidence supporting that inflammatory response constitutes the “common soil” of the multifactorial diseases, including cardiovascular and metabolic diseases, psychotic neurodegenerative disorders and cancer (Scrivo et al., 2011).

传统认知中，炎症通常被认为是应对微生物侵袭或组织损伤的关键反应，以维持组织的平衡状态。近年来，我们对炎症作用的认识有了很大的提高。炎症通路已被公认为许多慢性疾病发病机制中一个关键的分子基础。到目前为止，越来越多的文献表明，过度的炎症在压力相关疾病的进展和/或发病中起着关键作用。越来越多的证据支持炎症反应构成了多因素疾病的“共同土壤”，包括心血管和代谢疾病，精神病性神经退行性疾病和癌症(Scrivo et al., 2011)。

Stress, Inflammation and Diseases

压力、炎症和疾病

Accumulating researches suggested that excessive inflammation plays critical roles in relationship between stress and stress-related diseases. Although stress and inflammation, or inflammation and diseases have been widely and nicely discussed, there are few literatures concerned of all these three factors (stress, inflammation and disease). In this part, we will discuss inflammation in different stress-related diseases and explore the inside mechanism (Table 1).

越来越多的研究表明，过度炎症在压力和与压力相关疾病之间起着关键作用。虽然压力和炎症，或炎症和疾病已经得到了广泛而很好的讨论，但很少有文献在同时关注这三个因素（压力，炎症和疾病）。在这一部分，我们将讨论不同压力相关疾病中的炎症，并探索其内部机制（表1）。

TABLE 1

Table 1. Stress substance that link stress and various diseases.

表1

表1：将压力和各种疾病联系起来的压力性物质

Stress, Inflammation and CVD

压力、炎症和心血管疾病

CVD was considered to be a leading cause of death worldwide. Large bodies of clinical trial pointed out that chronic stress, whether early life stress (Su et al., 2015) or adult stress has long been linked to increased coronary heart disease (CHD) risk. Childhood adversity especially severe physical and sexual abuse in childhood was found to strongly relate to higher morbidity of cardiovascular events in women (Rich-Edwards et al., 2012; Thurston et al., 2014). Children who are less expressive and cohesive in their original family exhibited more problematic cardiovascular risk factor profiles (Bleil et al., 2013). Those who experienced more family disruption events or early life family conflict had greater mean intima-media thickness (IMT), a subclinical marker of CVD risk (Bleil et al., 2013). In adulthood, work-related stressors such as low-income, high job demands combined with low control, shift work and workplace conflicts were mostly reported to be correlated to higher CVD risk (Bleil et al., 2013). Besides that, poor sleep quality under stress, discrimination emotion stress, such as anger, hostility and aggressiveness were also involved in coronary artery disease (Kop, 2003). On the contrast, effective stress management including positive emotions, optimism and life satisfaction were proved to have protective roles for CVD (Bleil et al., 2013).

心血管疾病被认为是在全世界范围内造成死亡的主要原因。大量的临床试验指出，慢性压力，无论是早期生活压力(Su et al., 2015)还是成年压力，长期以来都与冠心病（CHD）风险增加有关。童年逆境特别是儿童时期严重的身体和性虐待与女性心血管事件的发病率较高密切相关(Rich-Edwards et al., 2012; Thurston et al., 2014)。在原有家庭中表达力和凝聚力较差的儿童表现出更多的心血管危险因素特征(Bleil et al., 2013)。那些经历过更多家庭破裂事件或早期生活家庭冲突的人具有更大的平均内膜-中层厚度（IMT），这是CVD风险的亚临床标志物(Bleil et al., 2013)。在成年后，与工作相关的压力因素，如低收入，高工作需求，加上低控制度，轮班工作和工作场所冲突，大多与较高的CVD风险相关 (Bleil et al., 2013)。除此之外，在压力下睡眠质量差，歧视性情绪压力，如愤怒，敌意和攻击性也与冠状动脉疾病有关(Kop, 2003)。相比之下，有效的压力管理，包括积极的情绪，乐观和生活满意度被证实对CVD具有保护作用 (Bleil et al., 2013)。

While the biological mechanisms of stress increasing CVD risk are not well-known, chronic low-grade inflammatory load may emerge as a possible link as it is both elevated by chronic stress and contributed to early process, progression and thrombotic complications of atherosclerosis. IL-6 and CRP, the two important biomarkers of systematic inflammation, are considered indicative and potentially predictive for atherosclerosis (Tsirpanlis, 2005;Nadrowski et al., 2016). Coincidently, these two inflammatory indicators were elevated in different types of life stress. For instance, severe levels of childhood abuse were associated with a more elevated acute stress-induced IL-6 response, possibly due to reduced methylation of the IL-6 promoter (Janusek et al., 2017). Adults who had greater childhood adversity was reported to have more depressive symptoms and elevated concentrations of CRP (Janusek et al., 2017). Recent studies have suggested that CRP and IL-6 are mechanisms by which early adversity may contribute to CVD (Ridker et al., 2002; Albert et al., 2006; Graham et al., 2006). Work-related stressors have also been mentioned to correlate with elevated CRP and IL-6 (von Känel et al., 2008). In a recent study applied in black and white men, greater stressor-evoked reduction in high-frequency heart rate variability (HF-HRV) and were correlated with higher CRP and IL-6. In animal stress models (social isolation, social disruption, cold stress, severe chronic unpredictable stress), increased plaque size, elevated serum IL-6, NPY levels were observed. However, when single supplied with GC after Adrenalectomy, plaque size and serum inflammatory factors were decreased or did not change. This suggested that the possible mechanisms of stress-related inflammation in CVD may include SNS-mediated increases in NE and NPY. Noisy communities as life stressor induces significant increase in urine epinephrine and NE leading to hypertension (Seidman and Standring, 2010). NE promoted the production of inflammatory factors by facilitating the phosphorylation of MAPKs through activation of NE α receptor (Huang et al., 2012). NPY could elicit TGF-β1 and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (von Känel et al., 2008). NPY could also directly activate the HMGB1 release and cytoplasmic translocation from the macrophage (Zhou et al., 2013). Inflammation has also been shown to correlate with endothelial dysfunction and relate to the renin-angiotensin system (Li et al., 2012).

虽然压力增加心血管疾病风险的生物学机制尚不清楚，但慢性低度炎症性负荷可能成为一种潜在关联，因为它既因慢性压力而升高，又促成了动脉粥样硬化的早期过程，进展和血栓并发症。IL-6和CRP是系统性炎症的两个重要生物标志物，被认为对动脉粥样硬化具有指示性和潜在预测性(Tsirpanlis, 2005; Nadrowski et al., 2016)。巧合的是，这两种炎症指标在不同类型的生活压力下会随之升高。例如，严重的童年虐待与急性应激诱导的IL-6反应的升高有关，可能是由于IL-6启动子的甲基化程度降低了 (Janusek et al., 2017)。据报道，具有更大童年逆境的成年人具有更多的抑郁症状和更高的CRP浓度 (Janusek et al., 2017)。最近的研究表明，CRP和IL-6是早期逆境可能导致CVD的机制(Ridker et al., 2002; Albert et al., 2006; Graham et al., 2006)。工作相关的压力因素也被提到与CRP和IL-6的升高相关 (von Känel et al., 2008)。在最近应用于黑人和白人男性的研究中，更大的压力源诱发的高频心率变异性（HF-HRV）的减少与较高的CRP和IL-6相关联。在动物压力模型（社会孤立，社会混乱，寒冷压力，严重的慢性不可预测的压力）中，观察到斑块大小增加，血清IL-6升高，NPY水平升高。然而，当肾上腺切除术后单一供应GC时，斑块大小和血清炎症因子减少或没有改变。这表明心血管疾病中与压力相关的炎症的机制，可能包括SNS介导的NE和NPY的增加。嘈杂的社区作为生活压力源会诱发尿液中肾上腺素和NE显着增加，导致高血压 (Seidman and Standring, 2010)。NE通过激活NE α受体促进MAPKs的磷酸化来促进炎症因子的产生(Huang et al., 2012)。NPY可以通过Y1受体在巨噬细胞样细胞系RAW264.7中激发TGF-β1和TNFα的产生(von Känel et al., 2008)。NPY还可以直接激活巨噬细胞的HMGB1释放和细胞质转移 (Zhou et al., 2013)。炎症也被证实与内皮功能障碍相关，并与肾素 - 血管紧张素系统有关 (Li et al., 2013)。

Overall, the possible mechanism could be summarized as follows. Stress may activate through SNS system to release NE and NPY, these two stress hormones further facilitate the phosphorylation of MAPKs or HMGB1 release, therefore inducing systematic inflammation (IL-6, CRP) to promote or accelerate CVD development. Anti-inflammatory drugs may have synergistic effect with conventional antihypertensive drugs on the prevention and treatment of stress-related CVD.

总体而言，可能的机制可归纳如下。压力可以通过SNS系统激活，释放NE和NPY，这两种压力激素进一步促进MAPKs的磷酸化或HMGB1的释放，因此诱发系统性炎症（IL-6，CRP），促进或加速心血管疾病的发展。抗炎药可能与常规抗高血压药在预防和治疗压力相关的心血管疾病方面具有协同作用。

Stress, Inflammation and

Metabolic Disease

压力、炎症和代谢性疾病

Stressful events could motivate unhealthy food choices (Kuo et al., 2008). These unhealthy foods are frequently associated with morbid obesity, type 2 diabetes mellitus, metabolic syndrome and NAFLD (Mikolajczyk et al., 2009). Stress enhances both post-meal peaks of triglycerides and delays lipids clearance (Kiecolt-Glaser, 2010). As shown in Hoorn’s study, stressful life events, which indicate chronic psychological stress, are associated with higher prevalence of undetected type 2 diabetes (Mooy et al., 2000). A recent prospective study supported this view, and provided further evidence (Cosgrove et al., 2012). Furthermore, effective stress management training or mindfulness-based stress reduction training has been proved to have clinically significant benefits on patients with type 2 diabetes. On the contrary, highly anxious patients did not obtain more improvement from the training (Rosenzweig et al., 2007).

压力事件可能会促使人们选择不健康的食物(Kuo et al., 2008)。通常病态肥胖、2型糖尿病、代谢综合征及非酒精性脂肪肝都与这些不健康的食物相关(Mikolajczyk et al., 2009)。压力会增强餐后甘油三酯的峰值并延缓脂质清除 (Kiecolt-Glaser, 2010)。正如Hoorn的研究所示，未被发现的2型糖尿病的较高患病率与生活中的压力事件造成的长期心理压力有关(Mooy et al., 2000)。最近的一项前瞻性研究支持了这一观点，并提供了进一步的证据(Cosgrove et al., 2012)。此外，在临床上，有效的压力管理训练或基于正念的减压训练已被证实对2型糖尿病患者具有显著益处。相反，高度焦虑的患者没有从训练中获得更多的改善 (Rosenzweig et al., 2007)。

Insulin resistance frequently develops during acute or chronic stress (Tsuneki et al., 2013). Insufficient insulin secretion to compensate for insulin resistance is also the characteristic of Type 2 diabetes. Insulin resistance, visceral obesity, dyslipidemia, type 2 diabetes mellitus and metabolic syndrome are key risk factors in the development and progression of NAFLD. At the intersection of metabolism and immunity, inflammation may be an important link between stress and metabolic disease. Intense stress over-activates the immune system, leading to the imbalance between inflammation and anti-inflammation. The activated stress pathways can initiate or exacerbate inflammation and culminate in hepatocyte cell death and liver damage by apoptosis (Gentile et al., 2011). IL-1 family members might be involved in controlling insulin resistance and metabolic inflammation in various obesity-associated disorders (Kamari et al., 2011; Tilg and Moschen, 2011; Tack et al., 2012). It is reported that the modulator of IL-1, NLRP6 and NLRP3 inflammasomes negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome (Zhu et al., 2006). Inflammatory transcriptor NF-κB and JNK activator protein-1 (AP-1) emerged as a central metabolic regulator (Wellen and Hotamisligil, 2005). Enhanced hepatic NF-κB activity was observed in high fat fed-mice (Day, 2006). NAFLD is regularly associated with lipometabolic disorders and inflammatory reactions, especially in the nonalcoholic steatohepatitis (NASH) stage (Liu et al., 2012). Chronic, low-grade inflammatory process is also the characteristic of diabetes. The “two-hit” hypothesis for the pathogenesis of NAFLD implicates inflammation as the link between steatosis and steatohepatitis. Inflammatory stress may aggravate the progression of NAFLD by increasing cholesterol influx and reducing cholesterol efflux especially during the second-hit stage of NAFLD (Ma et al., 2008).

胰岛素抵抗经常在急性或慢性压力下发展 (Tsuneki et al., 2013)。补偿胰岛素抵抗的胰岛素分泌不足也是2型糖尿病的特征。胰岛素抵抗、内脏肥胖、血脂异常、2型糖尿病和代谢综合征是非酒精性脂肪肝发生和进展的关键风险因素。在代谢和免疫的交叉点上，炎症可能是压力和代谢疾病之间的一个重要环节。强烈的压力会过度激活免疫系统，导致炎症和抗炎之间的不平衡。被激活的应激通路可以引发或加剧炎症，并最终导致肝细胞死亡和细胞凋亡引起的肝损伤 (Gentile et al., 2011)。IL-1家族成员可能参与控制各种肥胖相关疾病中的胰岛素抵抗和代谢性炎症 (Kamari et al., 2011; Tilg and Moschen, 2011; Tack et al., 2012)）。据报道，IL-1，NLRP6和NLRP3炎症体的调节剂对非酒精性脂肪肝/非酒精性脂肪性肝炎的进展以及代谢综合征的多个方面进行了负向调节 (Zhu et al., 2006)。炎症转录因子NF-κB和JNK激活蛋白-1（AP-1）成为了中枢代谢的调节剂 (Wellen and Hotamisligil, 2005)。在高脂肪喂养小鼠中观察到肝脏NF-κB活性增强 (Day, 2006)。非酒精性脂肪肝通常与脂质代谢性疾病和炎症反应有关，特别是在非酒精性脂肪性肝炎（NASH）阶段 (Liu et al., 2012)。慢性、低级别的炎症过程也是糖尿病的特征。非酒精性脂肪肝发病机制的“双击”假说将炎症作为脂肪变性和脂肪性肝炎之间的联系。炎症压力可能通过增加胆固醇的流入和减少胆固醇的流出来加剧非酒精性脂肪肝的进展，特别是在非酒精性脂肪肝的第二重打击阶段(Ma et al., 2008)。

Metabolism-controlling stress hormones, especially GCs and NE could exert anti-insulin effects, and in the long run induce insulin resistance. GC receptor antagonist RU486 and adrenalectomy reduce the occurrence of insulin resistance. High concentration of NE in plasma could raise fasting glucose and reduce glucose tolerance, possibly mediated by lipolysis and increased fatty acid concentrations (Marangou et al., 1988). Adrenergic receptor activation may directly affect the insulin signaling pathway or cellular glucose transport (Mulder et al., 2005). Additionally, GCs and NE could also regulate inflammation. In diabetes, elevated circulating levels of proinflammatory cytokines are originally thought to be the adipocytes themselves in response to obesity. However, an increasing number of evidence suggests that obesity results in increased number of macrophages and changes in the activation status of these cells. Therefore, adipose tissue macrophages produce a significant proportion of the inflammatory factors that are upregulated by obesity (Donath and Shoelson, 2011). Inflammatory cytokines produced by various cells such as Kupffer cells, macrophages, neutrophils, monocytes, adipocytes and hepatocytes, have critical roles in lipid metabolism and hepatic inflammation that promote liver damage. Antagonizing or inhibiting TNFα, significantly improved NAFLD and is currently tested in human NASH (chronic hepatic inflammation; Gastaldelli et al., 2009; Musso et al., 2009). Furthermore, TNFR1 ectodomain shedding could attenuate the progression from “simple steatosis” towards NASH (Aparicio-Vergara et al., 2013).

控制代谢的应激激素，特别是GCs和NE可以发挥抗胰岛素的作用，从长远来看会诱发胰岛素抵抗。GC受体拮抗剂RU486和肾上腺切除术可减少胰岛素抵抗的发生。血浆中高浓度的NE可以提高空腹血糖并降低葡萄糖耐量，可能是由脂肪分解和脂肪酸浓度的增加所介导的 (Marangou et al., 1988)。肾上腺素受体的激活可能直接影响胰岛素信号通路或细胞葡萄糖转运(Mulder et al., 2005)。此外，GCs和NE也可以调节炎症。在糖尿病中，促炎症细胞因子的循环水平升高最初被认为是脂肪细胞本身对肥胖的反应。然而，越来越多的证据表明，肥胖会导致巨噬细胞数量的增加及其活化状态的变化。因此，脂肪组织巨噬细胞产生了相当一部分因肥胖而上调的炎症因子(Donath and Shoelson, 2011)。由各种细胞产生的炎症细胞因子，如Kupffer细胞，巨噬细胞，中性粒细胞，单核细胞，脂肪细胞和肝脏细胞，在促进肝损伤的脂质代谢和肝脏炎症中起着关键作用。拮抗或抑制TNFα，显着改善非酒精性脂肪肝，目前正在慢性肝炎人群中进行人体测试 (Gastaldelli et al., 2009; Musso et al., 2009)。此外，TNFR1外域脱落可以减弱从“单纯脂肪变性”向慢性肝炎的进展 (Aparicio-Vergara et al., 2013)。

未完待续

参考文献

滑动查看参考文献：

Albert M. A., Glynn R. J., Buring J., Ridker P. M. (2006). Impact of traditional and novel risk factors on the relationship between socioeconomic status and incident cardiovascular events. Circulation 114, 2619–2626. 10.1161/circulationaha.106.660043

Alley D. E., Seeman T. E., Ki Kim J., Karlamangla A., Hu P., Crimmins E. M. (2006). Socioeconomic status and C-reactive protein levels in the US population: NHANES IV. Brain Behav. Immun. 20, 498–504. 10.1016/j.bbi.2005.10.003

Angelo L. S., Talpaz M., Kurzrock R. (2002). Autocrine interleukin-6 production in renal cell carcinoma: evidence for the involvement of p53. Cancer Res. 62, 932–940.

Aparicio-Vergara M., Hommelberg P. P. H., Schreurs M., Gruben N., Stienstra R., Shiri-Sverdlov R., et al.. (2013). Tumor necrosis factor receptor 1 gain-of-function mutation aggravates nonalcoholic fatty liver disease but does not cause insulin resistance in a murine model. Hepatology 57, 566–576. 10.1002/hep.26046

Barbieri A., Bimonte S., Palma G., Luciano A., Rea D., Giudice A., et al.. (2015). The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo. Int. J. Oncol. 47, 527–534. 10.3892/ijo.2015.3038

Bellinger D. L., Millar B. A., Perez S., Carter J., Wood C., ThyagaRajan S., et al.. (2008). Sympathetic modulation of immunity: relevance to disease. Cell. Immunol. 252, 27–56. 10.1016/j.cellimm.2007.09.005

Bencherif M., Lippiello P. M., Lucas R., Marrero M. B. (2011). α7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell. Mol. Life Sci. 68, 931–949. 10.1007/s00018-010-0525-1

Bleil M. E., Adler N. E., Appelhans B. M., Gregorich S. E., Sternfeld B., Cedars M. I. (2013). Childhood adversity and pubertal timing: understanding the origins of adulthood cardiovascular risk. Biol. Psychol. 93, 213–219. 10.1016/j.biopsycho.2013.02.005

Brenner D. R., Fanidi A., Grankvist K., Muller D. C., Brennan P., Manjer J., et al.. (2017). Inflammatory cytokines and lung cancer risk in 3 prospective studies. Am. J. Epidemiol. 185, 86–95. 10.1093/aje/kww159

Busillo J. M., Azzam K. M., Cidlowski J. A. (2011). Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome. J. Biol. Chem. 286, 38703–38713. 10.1074/jbc.M111.275370

Calcia M. A., Bonsall D. R., Bloomfield P. S., Selvaraj S., Barichello T., Howes O. D. (2016). Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl) 233, 1637–1650. 10.1007/s00213-016-4218-9

Capuron L., Raison C. L., Musselman D. L., Lawson D. H., Nemeroff C. B., Miller A. H. (2003). Association of exaggerated HPA axis response to the initial injection of interferon-α with development of depression during interferon-α therapy. Am. J. Psychiatry 160, 1342–1345. 10.1176/appi.ajp.160.7.1342

Chen C.-H., Zhou W., Liu S., Deng Y., Cai F., Tone M., et al.. (2012). Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int. J. Neuropsychopharmacol. 15, 77–90. 10.1017/S1461145711000149

Chung Y.-C., Chang Y.-F. (2003). Serum interleukin-6 levels reflect the disease status of colorectal cancer. J. Surg. Oncol. 83, 222–226. 10.1002/jso.10269

Cohen S., Janicki-Deverts D., Miller G. E. (2007). Psychological stress and disease. JAMA 298, 1685–1687. 10.1001/jama.298.14.1685

Comi C., Carecchio M., Chiocchetti A., Nicola S., Galimberti D., Fenoglio C., et al.. (2010). Osteopontin is increased in the cerebrospinal fluid of patients with Alzheimer’s disease and its levels correlate with cognitive decline. J. Alzheimers Dis. 19, 1143–1148. 10.3233/JAD-2010-1309

Cosgrove M. P., Sargeant L. A., Caleyachetty R., Griffin S. J. (2012). Work-related stress and Type 2 diabetes: systematic review and meta-analysis. Occup. Med. (Lond) 62, 167–173. 10.1093/occmed/kqs002

Danese A., Pariante C. M., Caspi A., Taylor A., Poulton R. (2007). Childhood maltreatment predicts adult inflammation in a life-course study. Proc. Natl. Acad. Sci. U S A 104, 1319–1324. 10.1073/pnas.0610362104

Day C. P. (2006). Non-alcoholic fatty liver disease: current concepts and management strategies. Clin. Med. 6, 19–25. 10.7861/clinmedicine.6-1-19

Donath M. Y., Shoelson S. E. (2011). Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107. 10.1038/nri2925

Dowlati Y., Herrmann N., Swardfager W., Liu H., Sham L., Reim E. K., et al.. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457. 10.1016/j.biopsych.2009.09.033

Elenkov I. J. (2008). Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem. Int. 52, 40–51. 10.1016/j.neuint.2007.06.037

Gao S. P., Mark K. G., Leslie K., Pao W., Motoi N., Gerald W. L., et al.. (2007). Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856. 10.1172/jci31871

García-Bueno B., Caso J. R., Leza J. C. (2008). Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci. Biobehav. Rev. 32, 1136–1151. 10.1016/j.neubiorev.2008.04.001

Gastaldelli A., Harrison S. A., Belfort-Aguilar R., Hardies L. J., Balas B., Schenker S., et al.. (2009). Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50, 1087–1093. 10.1002/hep.23116

Gentile C. L., Nivala A. M., Gonzales J. C., Pfaffenbach K. T., Wang D., Wei Y., et al.. (2011). Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1710–R1722. 10.1152/ajpregu.00677.2010

Graham J. E., Christian L. M., Kiecolt-Glaser J. K. (2006). Stress, age, and immune function: toward a lifespan approach. J. Behav. Med. 29, 389–400. 10.1007/s10865-006-9057-4

Grimaldi L. M., Casadei V. M., Ferri C., Veglia F., Licastro F., Annoni G., et al.. (2000). Association of early-onset Alzheimer’s disease with an interleukin-1α gene polymorphism. Ann. Neurol. 47, 361–365. 10.1002/1531-8249(200003)47:3<361::AID-ANA12>3.0.CO;2-N

Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.-Y., Vallabhapurapu S., et al.. (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113. 10.1016/j.ccr.2009.01.001

Heikkilä K., Ebrahim S., Lawlor D. A. (2008). Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur. J. Cancer 44, 937–945. 10.1016/j.ejca.2008.02.047

Henry C. J., Huang Y., Wynne A., Hanke M., Himler J., Bailey M. T., et al.. (2008). Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflammation 5:15. 10.1186/1742-2094-5-15

Hirano T., Ishihara K., Hibi M. (2000). Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548–2556. 10.1038/sj.onc.1203551

Hoshino T., Namba T., Takehara M., Nakaya T., Sugimoto Y., Araki W., et al.. (2009). Prostaglandin E2 stimulates the production of amyloid-β peptides through internalization of the EP4 receptor. J. Biol. Chem. 284, 18493–18502. 10.1074/jbc.M109.003269

Huang J.-L., Zhang Y.-L., Wang C.-C., Zhou J.-R., Ma Q., Wang X., et al.. (2012). Enhanced phosphorylation of MAPKs by NE promotes TNF-α production by macrophage through α adrenergic receptor. Inflammation 35, 527–534. 10.1007/s10753-011-9342-4

Janusek L. W., Tell D., Gaylord-Harden N., Mathews H. L. (2017). Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: an epigenetic link. Brain Behav. Immun. 60, 126–135. 10.1016/j.bbi.2016.10.006

Jiang C. L., Lu C. L., Liu X. Y. (1998). The molecular basis for bidirectional communication between the immune and neuroendocrine systems. Domest. Anim. Endocrinol. 15, 363–369. 10.1016/s0739-7240(98)00026-5

Johnson M. (2006). Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J. Allergy Clin. Immunol. 117, 18–24; quiz 25. 10.1016/j.jaci.2005.11.012

Johnson J. D., Campisi J., Sharkey C. M., Kennedy S. L., Nickerson M., Greenwood B. N., et al.. (2005). Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295–1307. 10.1016/j.neuroscience.2005.06.090

Kamari Y., Shaish A., Vax E., Shemesh S., Kandel-Kfir M., Arbel Y., et al.. (2011). Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J. Hepatol. 55, 1086–1094. 10.1016/j.jhep.2011.01.048

Kerr L. R., Wilkinson D. A., Emerman J. T., Weinberg J. (1999). Interactive effects of psychosocial stressors and gender on mouse mammary tumor growth. Physiol. Behav. 66, 277–284. 10.1016/s0031-9384(98)00296-0

Kiecolt-Glaser J. K. (2010). Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge. Psychosom. Med. 72, 365–369. 10.1097/PSY.0b013e3181dbf489

Kim-Fuchs C., Le C. P., Pimentel M. A., Shackleford D., Ferrari D., Angst E., et al.. (2014). Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for β-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40–47. 10.1016/j.bbi.2014.02.019

Kim T.-H., Gill N. K., Nyberg K. D., Nguyen A. V., Hohlbauch S. V., Geisse N. A., et al.. (2016). Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling. J. Cell Sci. 129, 4563–4575. 10.1242/jcs.194803

Kolmus K., Tavernier J., Gerlo S. (2015). β2-Adrenergic receptors in immunity and inflammation: stressing NF-κB. Brain Behav. Immun. 45, 297–310. 10.1016/j.bbi.2014.10.007

Kop W. J. (2003). The integration of cardiovascular behavioral medicine and psychoneuroimmunology: new developments based on converging research fields. Brain Behav. Immun. 17, 233–237. 10.1016/s0889-1591(03)00051-5

Krizanova O., Babula P., Pacak K. (2016). Stress, catecholaminergic system and cancer. Stress 19, 419–428. 10.1080/10253890.2016.1203415

Kunjathoor V. V., Tseng A. A., Medeiros L. A., Khan T., Moore K. J. (2004). β-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins. J. Neuroinflammation 1:23. 10.1186/1742-2094-1-23

Kuo L. E., Czarnecka M., Kitlinska J. B., Tilan J. U., Kvetnanský R., Zukowska Z. (2008). Chronic stress, combined with a high-fat/high-sugar diet, shifts sympathetic signaling toward neuropeptide Y and leads to obesity and the metabolic syndrome. Ann. N Y Acad. Sci. 1148, 232–237. 10.1196/annals.1410.035

Lamkin D. M., Sloan E. K., Patel A. J., Chiang B. S., Pimentel M. A., Ma J. C. Y., et al.. (2012). Chronic stress enhances progression of acute lymphoblastic leukemia via β-adrenergic signaling. Brain Behav. Immun. 26, 635–641. 10.1016/j.bbi.2012.01.013

Lamkin D. M., Sung H. Y., Yang G. S., David J. M., Ma J. C. Y., Cole S. W., et al.. (2015). α2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology 51, 262–270. 10.1016/j.psyneuen.2014.10.004

Landsbergis P. A. (2003). The changing organization of work and the safety and health of working people: a commentary. J. Occup. Environ. Med. 45, 61–72. 10.1097/00043764-200301000-00014

Li G., Xu Y., Ling F., Liu A., Wang D., Wang Q., et al.. (2012). Angiotensin-converting enzyme 2 activation protects against pulmonary arterial hypertension through improving early endothelial function and mediating cytokines levels. Chin. Med. J. 125, 1381–1388.

Lin Y., Yang X., Liu W., Li B., Yin W., Shi Y., et al.. (2017). Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation. Oncogene [Epub ahead of print]. 10.1038/onc.2016.516

Lippitz B. E. (2013). Cytokine patterns in patients with cancer: a systematic review. Lancet. Oncol. 14, e218–e228. 10.1016/S1470-2045(12)70582-X

Liu Y., Qiu D. K., Ma X. (2012). Liver X receptors bridge hepatic lipid metabolism and inflammation. J. Dig. Dis. 13, 69–74. 10.1111/j.1751-2980.2011.00554.x

Ma K. L., Ruan X. Z., Powis S. H., Chen Y., Moorhead J. F., Varghese Z. (2008). Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 48, 770–781. 10.1002/hep.22423

Mace T. A., Shakya R., Pitarresi J. R., Swanson B., McQuinn C. W., Loftus S., et al.. (2016). IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut [Epub ahead of print]. 10.1136/gutjnl-2016-311585

Mantyh P. W., Rogers S. D., Allen C. J., Catton M. D., Ghilardi J. R., Levin L. A., et al.. (1995). β 2-adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit and human. J. Neurosci. 15, 152–164.

Marangou A. G., Alford F. P., Ward G., Liskaser F., Aitken P. M., Weber K. M., et al.. (1988). Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis. Metab. Clin. Exp. 37, 885–891. 10.1016/0026-0495(88)90124-2

Mikolajczyk R. T., El Ansari W., Maxwell A. E. (2009). Food consumption frequency and perceived stress and depressive symptoms among students in three European countries. Nutr. J. 8:31. 10.1186/1475-2891-8-31

Miller G. E., Chen E., Sze J., Marin T., Arevalo J. M. G., Doll R., et al.. (2008). A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272. 10.1016/j.biopsych.2008.03.017

Miller A. H., Maletic V., Raison C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. 10.1016/j.biopsych.2008.11.029

Miura H., Ozaki N., Sawada M., Isobe K., Ohta T., Nagatsu T. (2008). A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress 11, 198–209. 10.1080/10253890701754068

Mooy J. M., de Vries H., Grootenhuis P. A., Bouter L. M., Heine R. J. (2000). Major stressful life events in relation to prevalence of undetected type 2 diabetes: the Hoorn Study. Diabetes Care 23, 197–201. 10.2337/diacare.23.2.197

Morand E. F., Leech M. (1999). Glucocorticoid regulation of inflammation: the plot thickens. Inflamm. Res. 48, 557–560. 10.1007/s000110050503

Mulder A. H., Tack C. J., Olthaar A. J., Smits P., Sweep F. C. G. J., Bosch R. R. (2005). Adrenergic receptor stimulation attenuates insulin-stimulated glucose uptake in 3T3–L1 adipocytes by inhibiting GLUT4 translocation. Am. J. Physiol. Endocrinol. Metab. 289, E627–E633. 10.1152/ajpendo.00079.2004

Munhoz C. D., García-Bueno B., Madrigal J. L. M., Lepsch L. B., Scavone C., Leza J. C. (2008). Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz. J. Med. Biol. Res. 41, 1037–1046. 10.1590/s0100-879x2008001200001

Musso G., Gambino R., Pacini G., De Michieli F., Cassader M. (2009). Prolonged saturated fat-induced, glucose-dependent insulinotropic polypeptide elevation is associated with adipokine imbalance and liver injury in nonalcoholic steatohepatitis: dysregulated enteroadipocyte axis as a novel feature of fatty liver. Am. J. Clin. Nutr. 89, 558–567. 10.3945/ajcn.2008.26720

Nadrowski P., Chudek J., Skrzypek M., Puzianowska-Kuźnicka M., Mossakowska M., Wiecek A., et al.. (2016). Associations between cardiovascular disease risk factors and IL-6 and hsCRP levels in the elderly. Exp. Gerontol. 85, 112–117. 10.1016/j.exger.2016.10.001

Nagatsu T., Sawada M. (2005). Inflammatory process in Parkinson’s disease: role for cytokines. Curr. Pharm. Des. 11, 999–1016. 10.2174/1381612053381620

Nicoll J. A., Mrak R. E., Graham D. I., Stewart J., Wilcock G., MacGowan S., et al.. (2000). Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann. Neurol. 47, 365–368. 10.1002/1531-8249(200003)47:3<365::AID-ANA13>3.3.CO;2-7

Norman G. J., Karelina K., Zhang N., Walton J. C., Morris J. S., Devries A. C. (2010). Stress and IL-1β contribute to the development of depressive-like behavior following peripheral nerve injury. Mol. Psychiatry 15, 404–414. 10.1038/mp.2009.91

Padro C. J., Sanders V. M. (2014). Neuroendocrine regulation of inflammation. Semin. Immunol. 26, 357–368. 10.1016/j.smim.2014.01.003

Park H. J., Lee P. H., Ahn Y. W., Choi Y. J., Lee G., Lee D.-Y., et al.. (2007). Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur. J. Neurosci. 26, 79–89. 10.1111/j.1460-9568.2007.05636.x

Peng Y.-L., Liu Y.-N., Liu L., Wang X., Jiang C.-L., Wang Y.-X. (2012). Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress. J. Neuroinflammation 9:75. 10.1186/1742-2094-9-75

Perez Nievas B. G., Hammerschmidt T., Kummer M. P., Terwel D., Leza J. C., Heneka M. T. (2011). Restraint stress increases neuroinflammation independently of amyloid β levels in amyloid precursor protein/PS1 transgenic mice. J. Neurochem. 116, 43–52. 10.1111/j.1471-4159.2010.07083.x

Pérez-Nievas B. G., García-Bueno B., Caso J. R., Menchén L., Leza J. C. (2007). Corticosterone as a marker of susceptibility to oxidative/nitrosative cerebral damage after stress exposure in rats. Psychoneuroendocrinology 32, 703–711. 10.1016/j.psyneuen.2007.04.011

Perry V. H., Cunningham C., Holmes C. (2007). Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167. 10.1038/nri2015

Pierce B. L., Ballard-Barbash R., Bernstein L., Baumgartner R. N., Neuhouser M. L., Wener M. H., et al.. (2009). Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J. Clin. Oncol. 27, 3437–3444. 10.1200/JCO.2008.18.9068

Qin J., Jin F., Li N., Guan H., Lan L., Ni H., et al.. (2015). Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 48, 295–300. 10.5483/bmbrep.2015.48.5.008

Quan N., Banks W. A. (2007). Brain-immune communication pathways. Brain Behav. Immun. 21, 727–735. 10.1016/j.bbi.2007.05.005

Raison C. L., Borisov A. S., Woolwine B. J., Massung B., Vogt G., Miller A. H. (2010). Interferon-α effects on diurnal hypothalamic–pituitary–adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol. Psychiatry 15, 535–547. 10.1038/mp.2008.58

Rich-Edwards J. W., Mason S., Rexrode K., Spiegelman D., Hibert E., Kawachi I., et al.. (2012). Physical and sexual abuse in childhood as predictors of early-onset cardiovascular events in women. Circulation 126, 920–927. 10.1161/CIRCULATIONAHA.111.076877

Ridker P. M., Rifai N., Rose L., Buring J. E., Cook N. R. (2002). Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med. 347, 1557–1565. 10.1056/nejmoa021993

Rohleder N. (2014). Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom. Med. 76, 181–189. 10.1097/PSY.0000000000000049

Rose-John S. (2012). IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int. J. Biol. Sci. 8, 1237–1247. 10.7150/ijbs.4989

Rosenzweig S., Reibel D. K., Greeson J. M., Edman J. S., Jasser S. A., McMearty K. D., et al.. (2007). Mindfulness-based stress reduction is associated with improved glycemic control in type 2 diabetes mellitus: a pilot study. Altern. Ther. Health Med. 13, 36–38.

Salgado R., Junius S., Benoy I., Van Dam P., Vermeulen P., Van Marck E., et al.. (2003). Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int. J. Cancer 103, 642–646. 10.1002/ijc.10833

Schroder K., Tschopp J. (2010). The inflammasomes. Cell 140, 821–832. 10.1016/j.cell.2010.01.040

Scrivo R., Vasile M., Bartosiewicz I., Valesini G. (2011). Inflammation as “common soil” of the multifactorial diseases. Autoimmun. Rev. 10, 369–374. 10.1016/j.autrev.2010.12.006

Seidman M. D., Standring R. T. (2010). Noise and quality of life. Int. J. Environ. Res. Public Health 7, 3730–3738. 10.3390/ijerph7103730

Smith R. S. (1991). The macrophage theory of depression. Med. Hypotheses 35, 298–306. 10.1016/0306-9877(91)90266-2

Sorrells S. F., Caso J. R., Munhoz C. D., Sapolsky R. M. (2009). The stressed CNS: when glucocorticoids aggravate inflammation. Neuron 64, 33–39. 10.1016/j.neuron.2009.09.032

Steptoe A., Hamer M., Chida Y. (2007). The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav. Immun. 21, 901–912. 10.1016/j.bbi.2007.03.011

Sterling P., Eyer J. (1988). “Allostasis: a new paradigm to explain arousal pathology,” in Handbook of Life Stress, Cognition and Health, eds Fisher S., Reason J. (Oxford: John Wiley & Sons; ), 629–649.

Su S., Jimenez M. P., Roberts C. T. F., Loucks E. B. (2015). The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr. Cardiol. Rep. 17:88. 10.1007/s11886-015-0645-1

Szczepanska-Sadowska E., Cudnoch-Jedrzejewska A., Ufnal M., Zera T. (2010). Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases. J. Physiol. Pharmacol. 61, 509–521.

Tack C. J., Stienstra R., Joosten L. A. B., Netea M. G. (2012). Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol. Rev. 249, 239–252. 10.1111/j.1600-065X.2012.01145.x

Thaker P. H., Han L. Y., Kamat A. A., Arevalo J. M., Takahashi R., Lu C., et al.. (2006). Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939–944. 10.1038/nm1447

Theron A. J., Steel H. C., Tintinger G. R., Feldman C., Anderson R. (2013). Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting? Drug Des. Devel. Ther. 7, 1387–1398. 10.2147/DDDT.S50995

Thiem S., Pierce T. P., Palmieri M., Putoczki T. L., Buchert M., Preaudet A., et al.. (2013). mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J. Clin. Invest. 123, 767–781. 10.1172/JCI65086

Thurston R. C., Chang Y., Derby C. A., Bromberger J. T., Harlow S. D., Janssen I., et al.. (2014). Abuse and subclinical cardiovascular disease among midlife women: the study of women’s health across the nation. Stroke 45, 2246–2251. 10.1161/STROKEAHA.114.005928

Tilg H., Moschen A. R. (2011). IL-1 cytokine family members and NAFLD: neglected in metabolic liver inflammation. J. Hepatol. 55, 960–962. 10.1016/j.jhep.2011.04.007

Tsirpanlis G. (2005). Inflammation in atherosclerosis and other conditions: a response to danger. Kidney Blood Press. Res. 28, 211–217. 10.1159/000087121

Tsukuda K., Mogi M., Iwanami J., Min L.-J., Sakata A., Jing F., et al.. (2009). Cognitive deficit in amyloid-β-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-γ activation. Hypertension 54, 782–787. 10.1161/HYPERTENSIONAHA.109.136879

Tsuneki H., Tokai E., Sugawara C., Wada T., Sakurai T., Sasaoka T. (2013). Hypothalamic orexin prevents hepatic insulin resistance induced by social defeat stress in mice. Neuropeptides 47, 213–219. 10.1016/j.npep.2013.02.002

von Känel R., Bellingrath S., Kudielka B. M. (2008). Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers. J. Psychosom. Res. 65, 51–59. 10.1016/j.jpsychores.2008.02.007

Weber M. D., Frank M. G., Tracey K. J., Watkins L. R., Maier S. F. (2015). Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J. Neurosci. 35, 316–324. 10.1523/JNEUROSCI.3561-14.2015

Wellen K. E., Hotamisligil G. S. (2005). Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119. 10.1172/jci25102

Wohleb E. S., Delpech J.-C. (2016). Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences. Prog. Neuropsychopharmacol. Biol. Psychiatry [Epub ahead of print]. 10.1016/j.pnpbp.2016.04.013

Wong M.-L., Inserra A., Lewis M. D., Mastronardi C. A., Leong L., Choo J., et al.. (2016). Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol. Psychiatry 21, 797–805. 10.1038/mp.2016.46

Wyss-Coray T. (2006). Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med. 12, 1005–1015. 10.1038/nm1484

Zhang Y., Liu L., Peng Y.-L., Liu Y.-Z., Wu T.-Y., Shen X.-L., et al.. (2014). Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors. CNS Neurosci. Ther. 20, 119–124. 10.1111/cns.12170

Zhao L., Xu J., Liang F., Li A., Zhang Y., Sun J. (2015). Effect of chronic psychological stress on liver metastasis of colon cancer in mice. PLoS One 10:e0139978. 10.1371/journal.pone.0139978

Zhou J.-R., Xu Z., Jiang C.-L. (2008). Neuropeptide Y promotes TGF-β1 production in RAW264.7 cells by activating PI3K pathway via Y1 receptor. Neurosci. Bull. 24, 155–159. 10.1007/s12264-008-0130-6

Zhou J.-R., Zhang L.-D., Wei H.-F., Wang X., Ni H.-L., Yang F., et al.. (2013). Neuropeptide Y induces secretion of high-mobility group box 1 protein in mouse macrophage via PKC/ERK dependent pathway. J. Neuroimmunol. 260, 55–59. 10.1016/j.jneuroim.2013.04.005

Zhu C.-B., Blakely R. D., Hewlett W. A. (2006). The proinflammatory cytokines interleukin-1β and tumor necrosis factor-α activate serotonin transporters. Neuropsychopharmacology 31, 2121–2131. 10.1038/sj.npp.1301029

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