去乙酰化酶(sirtuins)与炎症和新陈代谢有关

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Sirtuins Link Inflammation and Metabolism


Vidula T. Vachharajani 维杜拉 · t · 瓦查拉贾尼,1,2 Tiefu Liu 刘,2,3 Xianfeng Wang 王,1Jason J. Hoth 杰森 · j · 霍斯,4 Barbara K. Yoza 芭芭拉 · k · 约扎,4 and 及Charles E. McCall 查尔斯 · e · 麦考尔1Show more展示更多Academic Editor: 学术编辑:Ethan M. Shevach 伊桑 · m · 舍瓦奇Received 收到23 Nov 2015 二零一五年十一月二十三日Accepted 接受30 Dec 2015 二零一五年十二月三十日Published 出版20 Jan 2016 二零一六年一月二十日

Abstract

摘要

Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1–7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to “defend and mend” against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to “defend” against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to “mend,” leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis.

Sirtuins (SIRT) ,首次在酵母中发现,作为 NAD + 依赖的表观遗传和代谢调节因子,在人体生理学和疾病中具有类似的活性。越来越多的证据支持,七成员哺乳动物去乙酰化酶家族(SIRT1-7)通过感知生物能量需求和应对细胞营养物质的变化来保护体内平衡。去乙酰化酶在应激反应中恢复体内平衡中起着关键作用。炎症是用来“防御和修补”来抵御入侵的生物体的。新出现的证据表明,新陈代谢和生物能量重编程直接导致炎症的连续过程; 内稳态恢复失败导致许多慢性和急性炎症性疾病。与氧化磷酸化相比,糖酵解能快速促进活性氧和 ATP 的产生,从而激活免疫系统以抵御入侵微生物。脂肪分解/脂肪酸氧化,是细胞保护/冬眠和细胞存活的必要条件,以便“修补” ,导致免疫抑制。急性/慢性炎症与改变的糖酵解和脂肪酸氧化有关,至少部分与 NAD + 依赖的去乙酰化酶有关。治疗靶向去乙酰化酶可能提供一个新的类炎症和免疫调节剂。本文综述了去乙酰化酶如何在炎症过程中整合代谢、生物能量学和免疫,以及在慢性炎症性疾病和脓毒症的极端应激反应中去乙酰化酶如何改善预后。

1. Introduction

1. 引言

Sirtuins are a highly conserved family of proteins [1]. The silent information regulator 2 (SIR2) gene was first described in budding yeast as a regulator of chromatin structure and named MAR1 (mating-type regulator 1) [2]. A set of four genes, SIR1–4 described later, replaced the name “MAR” with “SIR” [3]. Subsequently, SIR2 homologues were identified in bacteria, plants, and mammals, representing a large family of highly conserved proteins called “sirtuins” [4]. Sirtuins belong to class III histone deacetylase family of enzymes. There are 7 mammalian sirtuins with distinct protein structure, varied subcellular location, and unique functional properties. The requirement for NAD+ as a cosubstrate for SIR2 deacetylase activity suggests that sirtuins may have developed as energy sensors and the redox state of cells [4].

去乙酰化酶是一个高度保守的蛋白家族[1]。沉默信息调节因子2(SIR2)基因首次在芽殖酵母中被描述为染色质结构调节因子,命名为 MAR1(交配型调节因子1)[2]。一套四个基因,SIR1-4后来描述,取代名称“ MAR”与“ SIR”[3]。随后,在细菌、植物和哺乳动物中发现了 SIR2同源基因,它们代表了一个高度保守的蛋白质大家族,称为“ sirtuins”[4]。去乙酰化酶属于 III 类组蛋白脱乙酰酶。有7种哺乳动物去乙酰化酶具有不同的蛋白质结构、不同的亚细胞位置和独特的功能特性。对 NAD + 作为 SIR2去乙酰化酶活性辅基的要求表明 sirtuins 可能已经发展成为能量传感器和细胞的氧化还原状态[4]。

Metabolism is known to influence aging in rodents and a number of other species of organisms [59]. Several lines of evidence suggest that benefits of calorie restriction are mediated through sirtuins [1012]. The most convincing link between aging and sirtuins was established after the effects of aging on NAD+ were studied [13]. In addition to its role as a cofactor in many enzymatic processes, NAD+ regulates key metabolic processes. Sirtuins are NAD+ sensors. SIRT1 and SIRT6 are known aging related sirtuins. Evidence suggests that NAD+ levels are decreased in aging; NAD+ replenishment in aged mice restores mitochondrial homeostasis in a SIRT1 dependent manner [14]. SIRT6 deficient mice show signs of accelerated aging and early death from hypoglycemia [1516].

众所周知,新陈代谢会影响啮齿动物和其他一些生物体的衰老[5-9]。一些证据表明卡路里限制的益处是通过 sirtuins 介导的[10-12]。在研究了衰老对 NAD + 的影响之后,我们发现衰老和去乙酰化酶之间最有说服力的联系。除了其作为辅助因子的作用,在许多酶的过程中,NAD + 调节关键的代谢过程。去乙酰化酶是 NAD + 传感器。SIRT1和 SIRT6是已知的与衰老有关的去乙酰化酶。有证据表明,NAD + 水平在衰老过程中下降,而 NAD + 的补充在老年小鼠体内以 SIRT1依赖的方式恢复线粒体内稳态[14]。SIRT6缺陷小鼠显示出加速老化和低血糖早期死亡的迹象[15,16]。

Inflammation defends against severe stress responses and if successful must resolve. SIRT1, known as a major metabolic regulator, epigenetically reprograms inflammation by altering histones and transcription factors such as NFκB and AP1 [17]. Mounting evidence supports that inflammation sequentially links immune, metabolic, and mitochondrial bioenergy networks; sirtuins are essential regulators of these networks. This review focuses on how sirtuins contribute to dynamic shifts in immunity, metabolism, and bioenergy during inflammation and selective chronic and acute inflammatory diseases and may provide novel therapeutic targets.

炎症防御严重的压力反应,如果成功必须解决。SIRT1,作为一个主要的代谢调节因子,通过改变组蛋白和转录因子如 nf b 和 AP1,表观遗传性地重新修复炎症。越来越多的证据支持炎症依次连接免疫、新陈代谢和线粒体生物能网络; 去乙酰化酶是这些网络的重要调节因子。本文综述了去乙酰化酶在炎症和选择性慢性和急性炎症性疾病中如何促进免疫、代谢和生物能量的动态变化,并可能提供新的治疗靶点。

Several general concepts are relevant to the role of sirtuins in inflammation:(1)The requirement for NAD+ as cofactor supports sirtuin function in redox and bioenergy sensing.(2)While sirtuin-dependent deacetylation activities dominate our present understanding of the functional roles of sirtuins in inflammation, other attributes such as ADP ribosylation (SIRT4) and removal of succinyl, malonyl, and glutamyl groups from lysine residues (SIRT5) may be important in inflammation [1819].(3)Acetyl CoA levels and its support of histone-acetylation and other proteins are linked to nutritional status of cell. Fasted or survival state of cell utilizes protein deacetylation with SIRT [20].(4)SIRT effects on inflammation can be a double edged sword, since low levels accentuate early acute inflammation-related autotoxicity by increasing NFκB RelA/p65 activity, and prolonged increases in SIRT1 during late inflammation are associated with immunosuppression and increased mortality [21].

关于 sirtuins 在炎症中的作用,有几个概念是相关的: (1) NAD + 作为辅助因子的需求支持 sirtuin 在氧化还原和生物能量感知中的功能。(2)虽然 sirtuin 依赖的去乙酰化活性主导了我们目前对 sirtuins 在炎症中的功能作用的理解,但是其他的属性,如 ADP 核糖基化(SIRT4)和从赖氨酸残基(SIRT5)中去除琥珀酰、丙二酰和谷氨酰基可能在炎症中起重要作用[18,19]。(3)乙酰辅酶 a 水平及其对组蛋白乙酰化等蛋白质的支持与细胞的营养状况有关。细胞的禁食或存活状态利用蛋白质去乙酰化与 SIRT [20]。对炎症的 SIRT 效应可能是一把双刃剑,因为低水平通过增加 nf b RelA/p65的活性加重了早期急性炎症相关的自身毒性,而且晚期炎症期间 SIRT1的长时间增加与免疫抑制和死亡率的增加有关。

2. Inflammation and Metabolism

2. 炎症和新陈代谢

Evidence suggests that the sequential course of inflammation is linked with metabolism. Several recent studies have connected inflammation with glycolysis and fatty acids to provide nutritional needs of immune cells for fueling phase shifts after stress sensing [21].

有证据表明,炎症的连续过程与新陈代谢有关。最近的一些研究已经将炎症与糖酵解和脂肪酸联系起来,以提供免疫细胞的营养需求,为压力感应后的相位变化提供能量[21]。

Glycolysis was considered as strictly an anaerobic process until Warburg described aerobic glycolysis in cancer cells for the first time in 1927. Warburg showed that cancer cells, under normoxic conditions, undergo glycolysis and produce lactate. It was deemed, however, that leukocytes/macrophages do not simulate “cancer metabolism” [2223]. Although glycolysis is metabolically less efficient per molecule of glucose (a net gain of 2 ATP) compared to oxidative phosphorylation (net gain of 36 ATP), marked increases in glycolysis rapidly respond to high metabolic demands of effector immunity [24]. Glycolysis activates pentose phosphate pathway to aid bacterial killing via NADPH oxidase and also provides fatty acids and amino acids for anabolic processes of cell. Glycolysis and glucose fueling are regulated via increased expression of and genes regulating glycolysis [21]. Additionally, there is disruption of mitochondrial glucose oxidation by PDHK which deactivates mitochondrial PDH. Thus, there is decreased mitochondrial glucose oxidation resulting in increased lactate and pyruvate accumulation. This glycolysis surge and decrease in mitochondrial glucose oxidation are dependent upon HIF-1α[2526]. HIF-1α in turn is regulated by PKM2 and NF kappa B [2728]. Thus, HIF1-α provides a bridge between glucose metabolism and inflammation [29]. Sirtuins, especially SIRT6, are known to be a master regulator of glycolysis. Evidence suggests that SIRT6 is a corepressor of glycolysis [3031]. Thus, glucose use for glycolysis generates effector responses needed for microbial defense including (1) ROS generation from NOX proteins and release of antimicrobial proteins such as porins, (2) anabolic pathways coupled to nucleus acid, fatty acid, and protein synthetic pathways, and (3) aerobic and anaerobic glycolysis which also supply rapidly needed ATP from high glucose flux as well as very early pyruvate oxidation to feed electron transport chain. Later this fuel is shifted to fatty acids because of closure of the pyruvate portal.

糖酵解一直被认为是一个严格的无氧过程,直到1927年 Warburg 首次描述了癌细胞的有氧糖酵解。Warburg 指出,在正常条件下,癌细胞进行糖酵解并产生乳酸。然而,人们认为白细胞/巨噬细胞不能模拟“癌症代谢”[22,23]。虽然与氧化磷酸化相比,糖酵解的代谢效率较低(净增加2 ATP) ,但糖酵解的显著增加迅速响应了效应免疫的高代谢需求[24]。糖酵解活化磷酸戊糖途径,通过 NADPH 氧化酶帮助杀死细菌,还为细胞的合成过程提供脂肪酸和氨基酸。糖酵解和葡萄糖补给是通过增加表达和基因调节糖酵解[21]。此外,PDHK 还破坏了线粒体 PDH 对葡萄糖的氧化作用,使 PDH 失活。因此,有减少线粒体葡萄糖氧化导致增加乳酸和丙酮酸的积累。这种糖酵解的激增和线粒体葡萄糖氧化的减少依赖于 hif-1[25,26]。Hif-1依次受 PKM2和 NF kappa b 调节[27,28]。因此,hif1- 在葡萄糖代谢和炎症之间提供了一座桥梁[29]。Sirtuins,特别是 SIRT6,是众所周知的糖酵解主要调节因子。有证据表明 SIRT6是糖酵解的辅抑制因子[30,31]。因此,葡萄糖用于糖酵解产生微生物防御所需的效应器反应,包括: (1) NOX 蛋白产生活性氧和释放抗菌蛋白,如孔蛋白; (2)与核酸、脂肪酸和蛋白质合成途径耦合的合成途径; (3)有氧和无氧的糖酵解,它也快速地从高葡萄糖流量中提供所需的 ATP,以及早期的丙酮酸氧化以供给电子传递链。之后,由于丙酮酸门户的关闭,这种燃料被转移到脂肪酸中。

The switch away from high levels of reducing agents (e.g., NADH and NADPH) to NAD+ dominance supports the cellular “mending” pathway, which is a low ATP generating catabolic state. The anti-inflammatory response of macrophages (so-called M2) requires fatty acid oxidation [22]. We now know that a metabolism shifts from glycolysis to fatty acid oxidation in macrophages after LPS stimulation [223233]. This increase in fatty acid oxidation occurs via expression of PGC-1α and PGC-1β [34]. SIRT1 and SIRT6 regulate the metabolic switch in monocytes from glycolysis to fatty acid oxidation during adaptation to acute inflammation [30]. This catabolic state supports repressor not only M2 like monocytes and macrophages, but also T repressor cells.

从高水平还原剂(例如 NADH 和 NADPH)到 NAD + 优势的转换支持细胞“修补”通路,这是一种低 ATP 产生的分解代谢状态。巨噬细胞(即 M2)的抗炎反应需要脂肪酸氧化[22]。我们现在知道,脂多糖刺激巨噬细胞后,代谢从糖酵解转变为脂肪酸氧化[22,32,33]。这种脂肪酸氧化的增加是通过 pgc-1和 pgc-1的表达发生的。SIRT1和 SIRT6在急性炎症适应过程中调节单核细胞从糖酵解到脂肪酸氧化的代谢开关[30]。这种分解代谢状态不仅支持 M2样单核细胞和巨噬细胞,而且支持 t 型阻遏细胞。

The immunosuppression that accompanies severe systemic inflammation is generated by an inflexible persistence of the repressor homeostasis axis, which limits a secondary response to new stress—for example, like bacterial and viral original or secondary opportunistic infections (discussed subsequently).

伴随严重全身性炎症的免疫抑制是由阻遏物稳态轴的不灵活持久性产生的,它限制了对新的压力的继发反应ー例如,细菌和病毒的原始感染或继发的机会性感染(随后讨论)。

3. Sirtuins and Chronic Inflammation

3. 去乙酰化酶与慢性炎症

Normal physiologic processes are accompanied by changes in levels and activity of sirtuins [35]. For example, circadian rhythm is controlled by NAD+ generation and cyclical activation and deactivation of SIRT1 and SIRT6. The circadian clock can influence chronic or acute inflammation [36].

正常的生理过程伴随着去乙酰化酶水平和活性的变化[35]。例如,昼夜节律受 NAD + 的产生以及 SIRT1和 SIRT6的周期性激活和失活控制。生物钟可以影响慢性或急性炎症[36]。

How do the functions of sirtuins contribute to chronic inflammation? Nuclear sirtuins SIRT1, SIRT6, and mitochondrial SIRT3—and likely other less well studied members of the sirtuin family—sense nutrient availability and changes in NAD+ production or ratios of NAD/NADH in macrophages or tissue cells. They then respond by reprogramming immune, metabolic, and bioenergy pathways [2137]. For example, SIRT1 supports insulin secretion in pancreatic β cells [38], gluconeogenesis in hepatocytes [39], and lipolysis/fatty acid oxidation in macrophages [40].

去乙酰化酶的功能是如何导致慢性炎症的?核 sirtuins SIRT1、 SIRT6和线粒体 sirt3ー以及其他可能研究较少的 sirtuin 家族成员ーー感知营养物质的可利用性和巨噬细胞或组织细胞 NAD + 产生或 NAD/nadh 比值的变化。然后,它们通过重新编程免疫、代谢和生物能途径来作出反应[21,37]。例如,SIRT1支持胰腺细胞的胰岛素分泌,肝细胞的糖异生,巨噬细胞的脂肪分解/脂肪酸氧化。

While research on the role of SIRT in chronic inflammation is in a very early stage, mounting evidence shows that NAD+ levels and SIRT transcription and/or protein levels are persistently reduced in specific tissue during chronic inflammation. Examples include fat deposits in obesity with inflammation [41], brain in Alzheimer’s disease [42], and arterial inflammation in atherosclerosis, using several types of chronic inflammation. Not unexpectedly, chronic inflammation also is accompanied by increased levels of activated proinflammatory transcription factor NFκB RelA/p65 [43]. Since nuclear SIRT1 and SIRT6 deacetylate RelA/p65 and support its proteasome degradation, decreased nuclear SIRT1 or SIRT6 levels/activity increase NFκB RelA/p65 activity and amplify proinflammatory gene expression during chronic inflammation. Further supporting of a role of SIRT1 in chronic inflammation is that increasing NAD+ levels [1] or activating SIRT1 by the polyphenol resveratrol reduces chronic inflammation and rebalances metabolism and bioenergetics toward homeostasis [44].

虽然 SIRT 在慢性炎症中的作用的研究还处于非常早期的阶段,但是越来越多的证据表明,在慢性炎症期间,特定组织中 NAD + 水平和 SIRT 转录和/或蛋白质水平持续下降。例子包括肥胖伴有炎症的脂肪沉积,阿尔茨海默氏病伴有大脑的炎症,以及动脉粥样硬化伴有动脉炎症的几种慢性炎症。不出所料,慢性炎症还伴随着激活的促炎性转录因子神经纤维瘤 b RelA/p65水平的增加。由于 SIRT1和 SIRT6脱乙酰基 RelA/p65支持其蛋白酶体降解,减少核 SIRT1或 SIRT6水平/活性增加 nf b RelA/p65活性,增加慢性炎症过程中促炎症基因的表达。进一步支持 SIRT1在慢性炎症中的作用的是,提高 NAD + 水平[1]或通过多酚白藜芦醇激活 SIRT1可以减少慢性炎症和重新平衡代谢以及使生物能量朝向稳态[44]。

A schematic representation of relationship between chronic inflammation and sirtuin expression/activity is depicted in Figure 1.

图1描述了慢性炎症和 sirtuin 表达/活性之间关系的示意图。

Figure 1 图1Sirtuins and chronic inflammation: during homeostasis (grey arrow), there are small perturbations in sirtuin levels without inflammation. During chronic inflammatory states (denoted by pink), persistent decreases in SIRT1 levels/activity sustain glycolysis-dependent proinflammatory pathways. This immunometabolic inflexibility alters the bioenergy homeostasis set point, which is rebalanced by increasing SIRT1 activity. Sirtuin 和慢性炎症: 在体内平衡期间(灰色箭头) ,sirtuin 水平没有炎症的小扰动。在慢性炎症状态(表示为粉红色) ,SIRT1水平/活性持续下降维持糖酵解依赖的前炎症通路。这种免疫合成代谢不灵活性改变了生物能量稳态设定点,该设定点是通过增加 SIRT1活性来重新平衡的

3.1. Examples of Sirtuin Links to Chronic Inflammatory Diseases
3.1. Sirtuin 与慢性炎症疾病的关连例子
3.1.1. Obesity, Diabetes, and Metabolic Syndrome
3.1.1. 肥胖、糖尿病和代谢症候群

In mature adipocytes, PPAR-γ regulates genes involved in fatty acid uptake and triglyceride synthesis to increase white adipose tissue (WAT) capacity to store fat [39]. SIRT1 suppresses PPAR-γ and decreases accumulation of fat. In obesity, with increased number and size of adipocytes, there is a decrease in SIRT1 levels and activity. Increased adiposity leads to increased adipose tissue macrophages prone to secreting TNF-α, IL-6, and iNOS, with heightened inflammation [45]. Thus, obesity is associated with low SIRT1 activity, increased inflammatory response, and expansion of WAT [3946].

在成熟脂肪细胞中,ppar- 调节与脂肪酸摄取和甘油三酯合成有关的基因,以增加白色脂肪组织储存脂肪的能力[39]。SIRT1抑制 ppar- 并减少脂肪的积累。在肥胖症中,随着脂肪细胞数量和大小的增加,SIRT1的水平和活性下降。肥胖症的增加导致脂肪组织中易于分泌肿瘤坏死因子-、白细胞介素 -6和诱导型一氧化氮合酶的巨噬细胞增加,并伴随着炎症的加剧[45]。因此,肥胖与低 SIRT1活性,增加炎症反应,以及 WAT 扩张有关[39,46]。

Literature suggests that SIRT1 counters insulin resistance [47]. Increased SIRT1 expression and activation elevate insulin secretion [38], while SIRT1 deficient mice show blunted insulin response to glucose stimulation. Mechanistically, SIRT1 promotes insulin secretion in pancreatic beta cells by repressing uncoupling protein UCP 2 expression [48]. In animal models of diabetes, SIRT1 activation increases energy expenditure and improves insulin sensitivity [4950]. Taken together, substantial data support that increased SIRT1 activity counters obesity, metabolic syndrome, and diabetes with or without obesity.

文献表明 SIRT1可以抑制胰岛素抵抗[47]。增加 SIRT1的表达和激活促进胰岛素分泌[38] ,而 SIRT1缺陷小鼠对葡萄糖刺激的胰岛素反应迟钝。机制上,SIRT1通过抑制解偶联蛋白 ucp2的表达来促进胰岛 β 细胞的胰岛素分泌。在糖尿病动物模型中,SIRT1激活增加能量消耗和改善胰岛素敏感性[49,50]。综合起来,大量数据支持 SIRT1活性的增加可以对抗肥胖症、代谢症候群和糖尿病,无论是否有肥胖症。

3.1.2. Atherosclerosis and Cardiovascular Diseases
3.1.2. 动脉粥样硬化与心血管疾病

Evidence supports an anti-inflammatory role for sirtuins in atherosclerosis. SIRT1 downregulates expression of the NFκB signaling pathway during atherosclerosis by deacetylating RelA/p65-NFκB in macrophages and decreasing foam cell formation [51]. The role of SIRT1 as a positive regulator of nuclear receptor and liver X receptor (LXR) that function as cholesterol sensors to regulate whole-body cholesterol and lipid homeostasis is evident from studies by Li et al. [52].

证据支持去乙酰化酶在动脉粥样硬化中的抗炎作用。SIRT1通过去乙酰化 rela/p65-nf b 在巨噬细胞中下调 nf b 信号通路的表达,减少泡沫细胞的形成[51]。在 Li 等人的研究中,SIRT1作为核受体和肝X受体(LXR)的积极调节因子的作用是显而易见的,LXR 作为胆固醇传感器来调节整个身体的胆固醇和脂质稳态。

Caloric restriction is shown to be associated with not only increased longevity, but also improved cardiovascular health [53]. Cardiovascular protective benefits of caloric restriction support SIRT1’s ability to promote lipolysis, improve insulin sensitivity, and limit proinflammatory macrophage activity [5254]. SIRT1 and SIRT3 activation reduces ischemia reperfusion injury in rodents [5456]; nuclear-cytoplasmic shuttling of SIRT1 plays an important role in this protection [57]. Thus, accumulating data supports an overall protective effect of SIRT1 activation on the chronic inflammation associated with atherosclerosis [5860].

热量限制被证明不仅能延长寿命,还能改善心血管健康。热量限制的心血管保护的好处支持 SIRT1的能力,促进脂解,提高胰岛素敏感性,并限制促炎性巨噬细胞活动[52,54]。SIRT1和 SIRT3的激活减轻了啮齿动物的缺血再灌注损伤[54-56] ; SIRT1的核质穿梭在这种保护中起重要作用[57]。因此,积累的数据支持 SIRT1激活对动脉粥样硬化相关的慢性炎症的整体保护作用[58-60]。

3.1.3. Alzheimer’s Disease
3.1.3. 老年痴呆症

Sirtuins contribute to chronic inflammation associated with Alzheimer’s disease and neurodegenerative diseases. The protective effect of caloric restriction with increased SIRT1 expression on Alzheimer’s disease was first reported in 2006 [42]. Consistent with a role for SIRT1 in brain dysfunction, animal models of ALS and Alzheimer’s disease respond to resveratrol induced SIRT1 activation by both promoting α-secretase nonamyloidogenic activity and attenuating Aβgeneration, a hallmark for Alzheimer’s disease [61]. Resveratrol delays the onset of Alzheimer’s disease and neurodegeneration [62] by decreasing plaque accumulation in rodents [63].

Sirtuins 导致阿尔茨海默病和神经退行性疾病相关的慢性炎症。限制热量摄入和增加 SIRT1表达对阿尔茨海默病的保护作用在2006年首次报道[42]。与 SIRT1在脑功能障碍中的作用一致,ALS 和阿尔茨海默病动物模型对白藜芦醇诱导的 SIRT1激活作出反应,通过促进分泌酶非淀粉样变性活性和减弱 a 代,a 代是阿尔茨海默病的标志[61]。白藜芦醇通过减少啮齿动物的斑块积累来延缓阿尔茨海默病和神经退行性疾病的发作。

3.1.4. Chronic Kidney Disease
3.1.4. 慢性肾病

Sirtuins regulate chronic renal inflammation. In cisplatin-induced chronic inflammatory kidney injury in animals, SIRT1 deacetylated NFκB RelA/p65 [64] and p53 [65] leading to reduced inflammation and apoptosis in an ischemia/reperfusion injury model [66]. Evidence also suggests administration of antioxidant agent acetyl-l-carnitine (AICAR) improves mitochondrial dynamics and protects mice from cisplatin-induced kidney injury in a SIRT3-dependent manner [67].

去乙酰化酶调节慢性肾脏炎症。在顺铂诱导的动物慢性炎症性肾损伤中,SIRT1去乙酰化 nf b RelA/p65[64]和 p53[65]在缺血/再灌注损伤模型中导致炎症和细胞凋亡减少[66]。还有证据表明,抗氧化剂乙酰肉碱(AICAR)可以改善线粒体动力学,并以 sirt3依赖的方式保护小鼠免受顺铂引起的肾损伤[67]。

3.1.5. Tobacco Smoke-Induced Inflammation
3.1.5. 烟草烟雾引起的炎症

Detailed studies of chronic inflammation associated with smoking implicate sirtuins in the process and support their potential role in prevention/intervention [68] and also implicated generation of reactive oxygen species in modifying the sirtuin axis [69]. SIRT1 deficient mice markedly amplify protein oxidation and lipid peroxidation induced by cigarette smoke. Genetic alterations of FOXO3 recapitulate these effects, and SIRT1 activation protects against smoke-induced lung injury. Improvement correlates with increased antioxidant activities of mitochondrial manganese superoxide dismutase (SOD2) and heme oxygenase 1 (HO1). SIRT1 and FOXO1 epigenetically control this balance in oxidation/reduction and ROS-dependent damage.

对与吸烟有关的慢性炎症的详细研究表明 sirtuins 参与了这一过程,并且支持了 sirtuins 在预防/干预中的潜在作用,同时也指出 sirtuin 轴被修饰的活性氧类。1缺陷的小鼠能显著增强香烟烟雾诱导的蛋白质氧化和脂质过氧化。FOXO3基因的改变概括了这些作用,SIRT1的激活对烟雾诱导的肺损伤具有保护作用。改善与线粒体超氧化物歧化酶(SOD2)和 HMOX1(HO1)抗氧化活性增强相关。SIRT1和 FOXO1表观遗传学上控制了氧化还原和 ros- 依赖性损伤的这种平衡。

3.1.6. Sirtuins and Other Mediators of Chronic Inflammatory Diseases
3.1.6. Sirtuins 及其他慢性炎症介质

It is important to emphasize that changes in SIRT1 or other sirtuins do not exist in isolation as a family of immunometabolic and bioenergy sensors and controllers of chronic inflammation. Most clearly documented are the connections between decreases in ATP with reciprocal increases in AMP with AMPK activation. SIRT1 and AMPK activation are commonly coupled and support reprogramming of shared pathways of metabolism and bioenergetics [70]; in some cases AMPK activation precedes that of SIRT1 and in others it follows. AMPK reduces anabolism by blocking protein synthesis via mTOR signaling. These interactions between SIRT redox sensing (NAD/NADH) and AMPK energy (ATP/ADP/AMP) sensing are at a crossroad for reducing glucose and protein synthesis proinflammatory anabolic processes and increasing fatty acid oxidation anti-inflammatory catabolic pathways. Dysregulation of this balance is a common feature of chronic inflammation.

必须强调的是,SIRT1或其他 sirtuins 的变化并不是孤立地作为免疫代谢和生物能量传感器家族和慢性炎症控制器存在的。最清楚的记录是 ATP 减少与腺苷酸正反增加与 AMPK 激活之间的联系。SIRT1和 AMPK 的激活通常是耦合的,支持新陈代谢和生物能量学共享途径的重编程; 在某些情况下,AMPK 的激活先于 SIRT1,在其他情况下,它紧随其后。AMPK 通过 mTOR 信号通路阻断蛋白质合成来降低合成代谢。SIRT 氧化还原传感(NAD/NADH)和 AMPK 能量传感(ATP/ADP/AMP)之间的相互作用,为降低葡萄糖和蛋白质合成促炎症合成过程,增加脂肪酸氧化抗炎分解途径提供了十字路口。这种平衡失调是慢性炎症的一个常见特征。

4. Sirtuins in Acute Inflammation

4. 急性炎症中的去乙酰化酶

Energy homeostasis maintains an intricate balance between cell nutrient sources and their storage (glycogen or triglyceride) or consumption (glycolysis or lipolysis) to meet cellular energy demands. For example, boundaries of basal homeostasis are temporarily exceeded and then restored during transient exercise, increased food intake, or fasting. Inflammatory reactions deviate from physiologic homeostasis boundaries and ultimately restore balance when successful [71]. Acute proinflammatory and immune effector pathways require increased glucose uptake, pentose phosphate pathway activation, and glycolysis leading to lactic acid accumulation. In a major stress response with acute systemic inflammation, this initial immune defensive pathway rapidly becomes autotoxic to cells and tissues by generating excessive ROS and prompting cell death pathways. These processes are described in detail below.

能量稳态维持细胞营养来源与其储存(糖原或甘油三酸酯)或消耗(糖酵解或脂解)之间的复杂平衡,以满足细胞能量需求。例如,在短暂的运动、增加食物摄入或禁食期间,基础平衡的界限会暂时超过,然后恢复。炎症反应偏离生理稳态界限,成功后最终恢复平衡[71]。急性促炎症和免疫效应通路需要增加葡萄糖摄取、磷酸戊糖途径激活和糖酵解导致乳酸堆积。在急性全身性炎症的主要应激反应中,这个最初的免疫防御通路通过产生过多的活性氧和促进细胞死亡通路迅速变成对细胞和组织的自毒性。下面将详细描述这些过程。

Unlike chronic inflammation, a major stress response with acute inflammation shifts from an anabolic glucose fueling aerobic glycolysis (Warburg response) to a fatty acid fueling catabolic/adaptation response. This fuel source enters mitochondria and generates acetyl CoA, which undergoes the tricarboxylic acid (TCA) cycle. The TCA cycle ultimately provides NADH and FADH as reducing agents for oxygen support of ATP generation. Importantly, the effector immune cell requires glycolysis as primary energy, whereas the repressor cell needs fatty acid. This concept emerges as a critical determinant of acute inflammatory injury and restoration of homeostasis and is a bedrock of the emerging concept of how metabolism and immunity are integrated based on bioenergy requirements.

与慢性炎症不同,急性炎症的主要应激反应从促进有氧糖酵解(Warburg 反应)的合成代谢葡萄糖转变为促进分解代谢/适应反应的脂肪酸。这个燃料来源进入线粒体并产生乙酰辅酶 a,它经历三元羧酸循环。TCA 循环最终提供 NADH 和 FADH 作为 ATP 生成的氧支持还原剂。重要的是,效应细胞的免疫细胞需要糖酵解作为主要能量,而阻遏细胞需要脂肪酸。这一概念成为急性炎症损伤和恢复体内平衡的关键决定因素,也是新陈代谢和免疫如何根据生物能量需求相结合这一新概念的基石。

Emerging data indicate that this “switch” from aerobic glycolysis to fatty acid fueling/adaptation response is modulated by sirtuins. We describe the role of SIRT1, SIRT3, and SIRT6 in subsequent sections in various conditions associated with acute inflammation.

新出现的数据表明,这种从有氧糖酵解到脂肪酸的“开关”加速了去乙酰化酶的适应反应。我们描述了 SIRT1,SIRT3,和 SIRT6在随后的各种条件下与急性炎症相关的作用。

4.1. Examples of Sirtuin Links to Acute Inflammatory Diseases
4.1. 与急性炎症性疾病相关的 Sirtuin 例子
4.1.1. Sirtuins in Acute Systemic Inflammation of Sepsis
4.1. 去乙酰化酶在脓毒症急性全身炎症中的作用

Sepsis is an example in which an extreme and highly lethal stress response induces marked deviations in homeostasis caused by an acute systemic inflammatory response. At an organism level, cardiovascular and microvascular functions are impaired leading to multiple organ failure. Within a few hours of sepsis and septic shock, the early initiating hyperinflammatory phase shifts to anti-inflammatory adaptation phase, which can persist for days to weeks in humans [7273]. Historically, the first recognition that extreme stress from bacterial products generates resistance to the products was endotoxin tolerance [74]. It is now known that endotoxin tolerance in neutrophils and monocyte/macrophages and dendritic cells frequently accompanies sepsis in humans and animals [7576]. Endotoxin tolerance, which is similar to the sepsis adaptation phase, requires changes in TLR-dependent signaling pathways, which culminate in epigenetic reprogramming of NFκB and other proinflammatory pathways [7678]. It is important to emphasize that endotoxin tolerance or adaptation develops very quickly [79]. Septic patients are likely to spend less than a day, if not only a few hours, in the cytokine storm of hyperinflammation. This quick switch makes it appear as if there is only one phase of human sepsis [80], which obscures sepsis molecular reprogramming and complicated treatment design and interpretations. Moreover, the acute systemic inflammation with sepsis prolongs the adaptation or immunometabolic phase, thereby generating clinically important immunosuppression [8182]. This has major implications for understanding the molecular basis of sepsis and its treatment.

脓毒症是一个例子,其中一个极端和高度致命的应激反应引起的急性全身炎症反应所造成的内环境平衡明显偏离。在机体水平,心血管和微血管功能受损导致多器官衰竭。在脓毒症和感染性休克的几个小时内,早期开始的高炎症阶段转变为抗炎适应阶段,这种适应阶段在人类中可持续数天至数周。从历史上看,最早认识到来自细菌产品的极端应激会产生对产品的抗性是内毒素耐受[74]。目前已知,中性粒细胞、单核/巨噬细胞和树突状细胞中的内毒素耐受常常伴随败血症在人类和动物中发生[75,76]。内毒素耐受与脓毒症适应期类似,需要 tlr 依赖的信号通路发生改变,最终导致 nf b 和其他促炎症通路的表观遗传重编程[76-78]。必须强调的是,内毒素耐受或适应性发展非常迅速[79]。脓毒症患者可能花不到一天,如果不是几个小时,在细胞因子风暴的重度炎症。这种快速的转变使得人类脓毒症似乎只有一个阶段,这模糊了脓毒症分子重编程和复杂的治疗设计和解释。此外,伴有败血症的急性全身性炎症延长了适应期或免疫代谢期,从而产生临床上重要的免疫抑制。这对于了解脓毒症的分子基础及其治疗具有重要意义。

The shift in NAD+ availability and decreased ATP availability during the transition from hyperinflammation to adaptation is the key to understanding the role of sirtuins in sepsis [83]. Increase in nuclear NAD+ activates SIRT1, which promotes gene silencing facultative heterochromatin formation at the promotors of proinflammatory genes such as TNF-α and IL-1β [3084]. Mechanistically, activated SIRT1 first directly binds and deactivates NF-κB RelA/p65 through deacetylation and proteasome degradation [85]. SIRT1 also induces RelB transcription and promotes its binding to NF-κB RelA/p65 sites, perhaps replacing RelA/p65. The SIRT1 and RelB partnership also deacetylates histone (H1) and recruits a multiunit repressor complex to form heterochromatin [2186].

在从炎症过渡到适应期间 NAD + 利用率的转变和 ATP 利用率的降低是了解 sirtuins 在脓毒症中的作用的关键[83]。增加核 NAD + 激活 SIRT1,促进基因沉默兼性异染色质形成的促炎症基因启动子,如 tnf- 和 il-1[30,84]。机制上,激活的 SIRT1首先通过脱乙酰化和蛋白酶体降解直接结合并失活 nf- b 相关蛋白 a/p65[85]。SIRT1还诱导 RelB 转录并促进其与 nf- b RelA/p65位点的结合,可能取代 RelA/p65位点。SIRT1和 RelB 的伙伴关系也去乙酰化组蛋白(H1) ,并招募多单位阻遏复合物形成异染色质[21,86]。

Acute inflammation-dependent immunometabolic reprogramming also requires communication between nuclear SIRT1 and SIRT6 [30]. Mechanistically, SIRT1 activation increases fatty acid flux, lipolysis, and fatty acid β oxidation in mitochondria by deacetylating and deactivating fork head box subgroup O (FOXO) family of transcription factors and other pathway regulators. This couples with activating nuclear receptors peroxisome proliferator-activated receptor gamma (PPAR-γ) by deacetylating PPAR-γ coactivator 1 alpha (PGC-1α). In a reciprocal process, SIRT6 directs deacetylation of histone H3K9 and hypoxia inducing factor alpha (HIF1-α), represses glucose flux and glycolysis, and limits pentose phosphate pathway-related oxidative (NADPH oxidase) and nonoxidative signaling (anabolism of nucleic acids). Thus, nuclear SIRT1 and SIRT6 acting through epigenetic chromatin are essential for switching glucose anabolic pathways to fatty acid oxidation catabolic pathways. This flexibility/polarity is required for inflammation to progress through its initiating effector phase to adaptation [2187]. This switch is essential for directing acute inflammation beyond the proinflammatory state typical of chronic inflammation, which appears to interfere with adaptation. Concomitant with this immune and metabolic switch, SIRT1 interactions with RelB induce transcription of mitochondrial SIRT3, which is needed in mitochondria to support SIRT1 dependent increases in fatty acid oxidation; SIRT3 is a master regulator of the majority of mitochondrial structural and functional proteins [88].

急性炎症依赖的免疫代谢重编程也需要核 SIRT1和 SIRT6之间的沟通[30]。机制上,SIRT1通过去乙酰化和去活化转录因子 o (FOXO)亚群和其他途径调节因子,增加线粒体中的脂肪酸通量、脂解和脂肪酸氧化。这与通过去乙酰化 ppar- 辅激活因子1 α (pgc-1)激活的核受体过氧化物酶体增殖物活化受体γ (ppar-)相联系。SIRT6通过相互作用,引导组蛋白 H3K9和缺氧诱导因子 α (hif1-)的去乙酰化,抑制葡萄糖通量和糖酵解,限制戊糖磷酸途径相关的氧化酶(NADPH 氧化酶)和非氧化信号转导(核酸的合成代谢)。因此,细胞核 SIRT1和 SIRT6通过表观遗传染色质发挥作用,是转换葡萄糖合成途径到脂肪酸氧化分解途径的关键。这种灵活性/极性是炎症通过其启动效应器阶段进展到适应所必需的[21,87]。这种转换对于引导急性炎症超越典型的慢性炎症的促炎症状态至关重要,慢性炎症似乎干扰适应。伴随着这种免疫和代谢开关,SIRT1与 RelB 的相互作用诱导线粒体 SIRT3的转录,这是线粒体内支持 SIRT1依赖的脂肪酸氧化增加所必需的,SIRT3是大多数线粒体结构和功能蛋白的主要调节因子[88]。

We have studied the role of SIRT1 in rodent sepsis with the focus on microvasculature. We also have shown that similar to the cell models of sepsis there are three distinct phases in the microvasculature of rodent sepsis: the hyperinflammatory/endotoxin responsive phase in early sepsis, a hypoinflammatory/endotoxin tolerant phase in late sepsis [79], and with return of endotoxin responsiveness in resolution phase in survivors.

我们以微血管为重点,研究了 SIRT1在鼠脓毒症中的作用。我们还发现,与败血症细胞模型相似,动物败血症的微血管有三个不同的阶段: 早期败血症的高炎症/内毒素反应期,晚期败血症的高炎症/内毒素耐受期[79] ,存活者的内毒素反应期恢复到消退期。

We show that the SIRT1 levels are increased during the hypoinflammatory (endotoxin tolerant: adaptation) phase of sepsis adaptation in mice. Importantly, SIRT1 inhibition with a specific inhibitor during the adaptation state significantly improves survival, concomitant with early reversal of microvascular endotoxin tolerance and decreased bacterial load [79]. Along with reversal of endotoxin tolerance, SIRT1 inhibition reshifts fatty acid oxidation to glycolysis in septic mouse splenocytes and human blood monocytes [37]. Together, these data emphasize the crucial role that sirtuins play in generating and prolonging adaptation and immunosuppression during the severe stress response of acute systemic inflammation from sepsis.

我们发现,SIRT1水平在小鼠脓毒症适应的低温期(内毒素耐受: 适应)增加。重要的是,在适应状态下,SIRT1与特异性抑制剂一起抑制可显著提高存活率,同时早期逆转微血管内毒素耐受性,减少细菌负荷[79]。随着内毒素耐受逆转,SIRT1抑制脂肪酸氧化重新转移到脓毒症小鼠脾细胞和人血单核细胞糖酵解[37]。总之,这些数据强调了去乙酰化酶在脓毒症引起的急性全身炎症的严重应激反应中产生和延长适应和免疫抑制的关键作用。

As an axis of immunometabolic regulation of acute inflammation, low levels of SIRT1 amplify the initial stage of acute inflammation, at least in part by increasing NFκB RelA/p65 activity. Accordingly, SIRT1 activation before sepsis onset or preceding administration of bacterial endotoxin protects against the initial “hyperinflammation” of sepsis. In the endotoxin shock model, resveratrol, a putative SIRT1 activator, decreases the initial inflammatory response [83]. Calorie restriction with increased SIRT1 improves outcome in polymicrobial sepsis in mice via activation of SIRT1 [89]. A schematic representation of relationship between acute inflammation and sirtuin expression/activity is depicted in Figure 2.

SIRT1作为急性炎症的免疫代谢调节轴,低水平的 SIRT1增强了急性炎症的初始阶段,至少部分增加了 nf b RelA/p65的活性。因此,SIRT1在脓毒症发病之前或之前给予细菌内毒素对脓毒症最初的“高炎症”有保护作用。在内毒素休克模型中,白藜芦醇,一个假定的 SIRT1激活剂,降低了最初的炎症反应[83]。增加 SIRT1的卡路里限制通过激活 SIRT1改善小鼠多微生物脓毒症的预后。图2描述了急性炎症和 sirtuin 表达/活性之间关系的示意图。

Figure 2 图2Sirtuins and acute inflammation of sepsis: the extreme stress response of sepsis rapidly induces a systemic and potentially lethal hyperinflammatory state (red), which shifts within hours to a counterreactive hypoinflammation/adaptation phase (blue). NAD+ activation of sirtuins directs this switch. Mechanistically, nuclear SIRT1 levels briefly drop when homeostasis deviation initiates the glycolysis-dependent hyperinflammation, but within hours nuclear and mitochondrial sirtuin activation shifts glycolysis to fatty acid oxidation. This metabolic reprogramming globally represses immunity, affecting neutrophils, monocytes, dendritic cells, NK cells, and T lymphocytes. Resolution of acute inflammation and sepsis rebalances sirtuins and inflammation to restore homeostasis. Persistent elevation of sirtuins and hypoinflammation as a result lead to death (denoted by light blue area). 去乙酰化酶与脓毒症急性炎症: 脓毒症的极端应激反应迅速诱发全身性和潜在致死性高炎症状态(红色) ,在数小时内转变为反应性低血压易燃/适应期(蓝色)。去乙酰化酶的 NAD + 激活引导这个开关。机制上,当体内平衡偏差引发糖酵解依赖性的重度炎症时,细胞核 SIRT1水平短暂下降,但几小时内,细胞核和线粒体 sirtuin 激活将糖酵解转变为脂肪酸氧化。这种全球性的代谢重编程抑制免疫,影响中性粒细胞、单核细胞、树突状细胞、 NK 细胞和 t 淋巴细胞。解决急性炎症和败血症重新平衡 sirtuins 和炎症,以恢复内环境稳定。持续升高的去乙酰化酶和低点燃导致死亡(表示淡蓝色区域)

4.1.2. Obesity and Acute Inflammation from Sepsis
4.1.2. 脓毒症引起的肥胖和急性炎症

As discussed, obesity with chronic inflammation and the metabolic syndrome are associated with reduced levels of SIRT1 [90]. We have found that SIRT1 deficient ob/ob mice show exaggerated microvascular inflammation during sepsis, which markedly increases mortality in comparison with lean mice [91]. As shown in Figure 3, sirtuin deficient obese mice show exaggerated hyperinflammatory phase of sepsis. We speculate that this exaggeration in hyperinflammation dictates prolongation of hypoinflammation/adaptation in sepsis. Moreover, pretreatment of ob/ob mice with resveratrol before sepsis reduces the accentuated microvascular inflammation and improves survival. The beneficial effect of resveratrol can be reversed by inhibiting SIRT1, supporting the amplified inflammatory response and perhaps high mortality in SIRT1 dependent manner [92].

如前所述,肥胖伴有慢性炎症和代谢症候群与 SIRT1水平降低有关。我们发现 SIRT1基因缺陷的 ob/ob 小鼠在脓毒症期间表现出明显的微血管炎症,与瘦小的小鼠相比明显增加了死亡率[91]。如图3所示,去乙酰化酶缺陷的肥胖小鼠显示了严重的脓毒症高炎症期。我们推测,这种高度炎症的夸张延长了脓毒症的低血压易燃/适应期。此外,在脓毒症前用白藜芦醇预处理的 ob/ob 小鼠,可以减轻加重的微血管炎症,提高存活率。白藜芦醇的有益作用可以通过抑制 SIRT1、支持扩增的炎症反应和依赖 SIRT1的高死亡率来逆转。

Figure 3 图3Sirtuins and obesity with sepsis: obesity is associated with low-sirtuin levels/activity, but mechanisms responsible for this imbalance are unknown. If sepsis occurs in obese individuals with low SIRT1, the early hyperinflammatory phase is accentuated and counteractive adaptation stage may be prolonged. Activating SIRT1 before obesity-associated sepsis prevents the accentuated acute inflammatory reaction. 去乙酰化酶和肥胖伴败血症: 肥胖与去乙酰化酶水平/活性低有关,但是造成这种不平衡的机制尚不清楚。如果 SIRT1水平低的肥胖患者发生脓毒症,早期高炎症期加重,反作用适应期可能延长。在肥胖相关性脓毒症发生前激活 SIRT1可以防止急性炎症反应的加重

4.1.3. Traumatic Lung Injury with Acute Inflammation
4.1.3. 创伤性肺损伤合并急性炎症

Traumatic injury induces an acute inflammatory response similar to that seen after acute infection and depends on TLR and NFκB-dependent transcriptional activation of IL-1β, TNF-α, and IL-6. In our model of traumatic lung injury, SIRT1 mRNA, protein, and activity are reduced for up to 24 hrs after injury [93]. In distinct contrast to immunosuppression observed after sepsis, trauma in this model sensitizes or “primes” the lung for a hyperinflammatory response to subsequent TLR stimulation, reflecting the clinically important “2nd hit response.” Resveratrol treatment prevents the trauma induced, neutrophil-dependent inflammatory response. Moreover, treating animals with resveratrol before the second hit rescues injured mice subjected to a TLR stimulus 24 hours after lung injury. Together, these data support that, like obesity with low SIRT1, acute trauma generates an inflammatory reaction in which insufficiently available SIRT1 leads to excessive inflammatory injury if an acute infection occurs.

外伤引起的急性炎症反应与急性感染后相似,依赖于 TLR 和 nf b 依赖的 il-1、 tnfα 和 IL-6的转录激活。在我们的创伤性肺损伤模型中,SIRT1的 mRNA、蛋白质和活性在损伤后24小时内下降[93]。与脓毒症后观察到的免疫抑制不同,这种模型中的创伤使肺对 TLR 刺激产生的高炎症反应敏感,反映了临床上重要的“第二击反应”白藜芦醇治疗预防创伤诱导,中性粒细胞依赖性炎症反应。此外,在第二次打击前用白藜芦醇治疗动物,可以救治肺损伤后24小时受 TLR 刺激的受伤小鼠。总之,这些数据支持,像肥胖低 SIRT1,急性创伤产生炎症反应,不足的 SIRT1导致过度炎症损伤,如果急性感染发生。

5. Summary

5. 总结

Substantial evidence supports that NAD+ dependent sirtuins play essential, but distinct, roles, in chronic and acute inflammation. Chronic inflammatory diseases often persist in a “low-sirtuin” state, and increasing SIRT1 levels or activity is beneficial. In acute inflammation, nuclear SIRT1 activation induces SIRT6 and SIRT3 and the combined functions of this nuclear-mitochondrial triad switch glycolysis to fatty acid oxidation and immunity from activation to repression. In the severe stress of sepsis, SIRT1 dependent control over immunometabolic reprogramming during adaptation, which counters the initial hyperinflammatory response, is prolonged. Sustaining the adaptation phenotype is supported by continued NAD+ generation coupled with increased SIRT1 expression and activation. This apparent inflexibility of adaptation during sepsis overrides inflammation resolution and homeostasis retrieval. SIRT1 dependent control over adaptation can be reversed in vitro by blocking SIRT1, which results in rebalanced mitochondrial fueling and restored immune competence. Moreover, blocking SIRT1 in septic mice during adaptation restores immune competence, rebalances mitochondrial bioenergetics, and improves survival.

大量证据支持 NAD + 依赖性去乙酰化酶在慢性和急性炎症中发挥重要而独特的作用。慢性炎症性疾病通常持续“低 sirtuin”状态,增加 SIRT1水平或活性是有益的。在急性炎症反应中,SIRT1的激活引起 SIRT6和 SIRT3的产生,这种核-线粒体三元开关糖酵解作用于脂肪酸氧化和免疫抑制作用。在严重的脓毒症应激状态下,SIRT1对适应期免疫代谢重编程的依赖性控制延长,而免疫代谢重编程与最初的高炎症反应相反。持续的 NAD + 的产生以及 SIRT1表达和激活的增加支持了适应表型的维持。脓毒症时这种明显的适应性缺陷超过了炎症消退和内稳态恢复。SIRT1通过阻断 SIRT1在体外可逆转对适应的依赖性控制,从而重新平衡线粒体补给并恢复免疫能力。此外,在脓毒症小鼠适应过程中阻断 SIRT1可恢复免疫能力,重新平衡线粒体生物能学,并提高存活率。

Better understanding of SIRT biology and its role in regulation of inflammation is in its infancy. Among the important unanswered questions are the following:(i)Do all sirtuin family members participate in immunometabolic reprogramming?(ii)What markers identify when to start anti-SIRT1 treatment for sepsis?(iii)What blocks “low SIRT1 states” from shifting to adaptation?(iv)What are the effects of SIRT1 modulators on various acute/chronic inflammatory conditions in patients with obesity/metabolic syndrome/aging/sepsis, and so forth?(v)What epigenetic/metabolic signatures occur during anti-SIRT1 sepsis rescue?(vi)What pathways link redox and ATP/AMP sensing?(vii)What informs the SIRT axis to shift from glycolysis to fatty acid oxidation?(viii)How is acute inflammation adaptation shift to resolution?(ix)What prevents “low SIRT1” proinflammatory states from entering adaptation?

对 SIRT 生物学及其在调节炎症中的作用的更好的理解还处于初级阶段。有待解决的重要问题包括: (一)是否所有 sirtuin 家族成员都参与免疫代谢重编程?什么标志物确定何时开始抗 sirt1治疗败血症?哪些因素阻碍了”低 SIRT1状态”向适应转变?(iv) SIRT1调节剂对肥胖/代谢综合症/老化/败血症等病人的各种急、慢性炎症状况有何影响?(v)在抗 sirt1败血症拯救过程中发生了哪些表观遗传/代谢特征?什么途径将氧化还原和 ATP/AMP 传感联系起来?(vii)是什么促使 SIRT 轴从糖酵解转向脂肪酸氧化?(八)急性炎症适应是如何转变为消除的?(ix)是什么阻止“低 SIRT1”促炎症状态进入适应?

Abbreviations

缩写

SIRT:Sirtuin
NAD+: NAD + :Nicotinamide dinucleotide 烟酰胺二核苷酸
SIR 2: 先生2:Silent information regulator 2 无声信息调节器2
ATP: 返回文章页面 ATP:Adenosine triphosphate 三磷酸腺苷
ADP: 自动数据处理:Adenosine dinucleotide Adenosine 二核苷酸
AMP: 安培:Adenosine monophosphate 单磷酸腺苷
Acetyl CoA: 乙酰辅酶 a:Acetyl coenzyme A 乙酰辅酶A
PPAR-γ:Peroxisome proliferator-activated receptor gamma 过氧化物酶体增殖物活化受体γ
PGC-1α:PPAR-γ coactivator 1 alpha 辅激活子1α
HIF-1 低氧诱导因子 -1α:Hypoxia inducing factor alpha 低氧诱导因子 α
NADPH:Nicotinamide adenine dinucleotide phosphate 烟酰胺腺嘌呤二核苷酸磷酸
UCP: 统一惯例:Uncoupling protein 解偶联蛋白
NF 神经纤维瘤κB: 乙:Nuclear factor 核因素κ B
ROS: 活性氧:Reactive oxygen species 活性氧类
AMPK:Adenosine monophosphate-activated protein kinase AMP活化蛋白激酶
mTOR:Mammalian target of rapamycin. 雷帕霉素哺乳动物靶

Conflict of Interests

利益冲突

The authors have no significant conflict of interests.

作者没有明显的利益冲突。

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