动物营养学报 >

2024 , Vol. 36 >Issue 10: 6191 - 6200

DOI: https://doi.org/10.12418/CJAN2024.527

综述

热应激诱导炎症反应及细胞自噬的调控机制

  • 罗烨 ,
  • 刘慧敏 ,
  • 瞿明仁 ,
  • 许兰娇 , *
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  • 江西农业大学动物科学技术学院,江西省动物营养重点实验室,营养饲料开发工程研究中心,南昌 330045
*许兰娇,副研究员,硕士生导师,E-mail:

罗 烨(2001—),男,湖南娄底人,硕士研究生,从事家禽营养研究。E-mail:

Copy editor: 田艳明

收稿日期: 2024-03-25

  网络出版日期: 2024-10-14

基金资助

国家自然科学基金项目(32060760)

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Regulatory Mechanism of Heat Stress-Induced Inflammatory Response and Autophagy

  • LUO Ye ,
  • LIU Huimin ,
  • QU Mingren ,
  • XU Lanjiao , *
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  • Engineering Research Center of Nutrient Feed Development, Jiangxi Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
*associate professor, E-mail:

Received date: 2024-03-25

  Online published: 2024-10-14

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摘要

自噬是真核细胞在自噬相关基因的调控下利用溶酶体降解自身细胞质蛋白和受损细胞器的过程,可防止组织细胞损伤。热应激可诱导炎症反应和自噬,炎症反应与自噬间相互调控,一方面,炎症的发生可抑制自噬水平,另一方面自噬通过负反馈调节炎症反应,三者间存在复杂的关系。营养与免疫间关系密切,本文从热应激诱导的炎症通路、自噬通路、热应激诱导的炎症与自噬间关系进行整理分析,旨在深入认识热应激、炎症与自噬间的关系,为通过营养调控手段增强自噬缓解热应激诱导炎症损伤提供一定的参考。

关键词： 热应激; 炎症反应; 细胞自噬; 炎症通路; 自噬通路

本文引用格式

罗烨 , 刘慧敏 , 瞿明仁 , 许兰娇 . 热应激诱导炎症反应及细胞自噬的调控机制[J]. 动物营养学报, 2024 , 36(10) : 6191 -6200 . DOI: 10.12418/CJAN2024.527

Abstract

Autophagy is a process in which eukaryotic cells use lysosomes to degrade their own cytoplasmic proteins and damaged organelles under the regulation of autophagy-related genes, which can prevent tissue and cell damage. Heat stress can induce inflammatory response and autophagy, and inflammatory response and autophagy regulate each other. On the one hand, the occurrence of inflammation can inhibit the level of autophagy, and on the other hand, autophagy regulates the inflammatory response through negative feedback. There is a complex relationship among the three relations. There is a close relationship between nutrition and immunity. This article summarizes and analyzes the relationship between heat stress-induced inflammation pathways, autophagy pathways, heat stress-induced inflammation and autophagy, aiming to gain a deeper understanding of the relationship between heat stress, inflammation and autophagy. Relationship, providing certain reference for enhancing autophagy to alleviate heat stress-induced inflammatory damage through nutritional regulation.

Key words： heat stress; inflammatory response; autophagy; inflammatory pathway; autophagy pathway

炎症性先天免疫反应在宿主防御病原体中是必不可少的,通过相关途径和反应保护宿主免受微生物感染。然而,炎症反应失调和过度会造成组织损伤。热应激是制约畜禽生产的重要因素之一,并通过多种途径介导炎症发生。其中主要通路涉及炎症小体——NOD样受体家族pyrin结构域包含3(NOD-like receptor family pyrin domain containing 3,NLRP3)的激活,而炎性小体是控制白细胞介素(interleukin,IL)-1家族成员成熟和产生的多蛋白复合物,在宿主防御病原体中起着至关重要的作用。许多国内外研究发现了炎症小体与自噬的相互调控[1]。自噬是一种主要的降解途径,它利用溶酶体水解酶降解细胞成分,通常在细胞应激条件下被诱导以恢复细胞稳态[2]。自噬能够调节炎症反应,比如受损的细胞器或组织可介导NLRP3炎症小体和非典型炎症小体的激活,而自噬可消除受损细胞器并负反馈调节炎症介导的IL-1家族成员的释放[3]。热应激可通过诱导自噬来缓解炎症反应的不利影响,但是持续的热应激会抑制自噬加重炎症损伤。热应激诱导、炎症与自噬间存在复杂的联系,本文将从热应激诱导炎症和自噬的几种途径进行分析,揭示热应激诱导的炎症反应和自噬的关系。

1 热应激诱导炎症的发生

1.1 炎症反应及主要信号通路

炎症是机体先天免疫系统对病原体和死细胞等有害刺激的一种免疫反应。核因子-κB(nuclear factor-κB,NF-κB)是一种诱导型转录因子,激活后诱导各种基因的转录,从而调节炎症反应。Toll样受体(Toll-like receptors,TLRs)是参与非特异性免疫的一类重要蛋白质分子,可以识别来源于微生物的具有保守结构的分子。丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是调节细胞多种生理过程的关键信号通路,包括增殖、分化、凋亡和应激反应。激活蛋白-1(activator protein-1,AP-1)是一种异二聚体蛋白转录因子,调节基因表达以响应多种外界信号,如细胞因子、生长因子、应激以及细菌和病毒感染。炎症通过多种因素的相互作用介导,但已知2种主要的信号通路:其一,炎症反应与活化NF-κB、TLRs和NLRP3炎性小体相关[4];其二,MAPK信号通路的激活诱导了AP-1的产生,AP-1在细胞核中转录增加了炎症反应[5]。
巨噬细胞是一大类先天免疫细胞,位于不同的组织中,在针对感染的免疫反应的前线发挥作用。模式识别受体(pattern recognition receptors,PRRs)可以通过病原体入侵诱导的病原体相关分子模式(pathogen-associated molecular patterns,PAMPs)来阻止先天免疫功能以及内应激诱导的损伤相关分子模式(damage-associated molecular patterns,DAMPs)。PRRs根据蛋白质结构域同源性可分为5种类型,其中TLRs在炎症反应中发挥重要作用。TLRs可识别肠道脂多糖(lipopolysaccharides,LPS)通过髓样分化因子88(myeloid differentiation factor 88,MyD88)适配器蛋白激活核因子-κB抑制物激酶(nuclear factor-κB inhibitor kinase,IKK)复合物。这导致核因子-κB抑制物(nuclear factor-κB inhibitor,IκB)蛋白的磷酸化和降解,释放NF-κB进入细胞核,进而诱导促炎基因的转录,如肿瘤坏死因子-α(TNF-α)、IL-6和IL-1等。此外,TLRs可识别PAMPs或DAMPs,通过MyD88适配器蛋白和其他分子,激活MAPK导致的一系列的磷酸化反应,最终激活转录因子,如AP-1,进一步促进促炎细胞因子的生成。在各种PAMPs和DAMPs的反应中,巨噬细胞迅速被激活并分泌大量细胞因子和趋化因子。在不同的病理生理条件下,活化的巨噬细胞能够分化成表型上不同的状态,包括经典活化(M1)和交替活化(M2)巨噬细胞。M1巨噬细胞的特征在于产生促炎细胞因子,如IL-1、IL-6、IL-12、TNF-α,以及趋化因子,参与各种炎症过程。M1巨噬细胞还促进炎性T细胞的分化,包括Th1和Th17细胞,进而介导炎症[6-7]。相比之下,M2巨噬细胞产生抗炎细胞因子,如IL-10和IL-13,对炎症消退和介导伤口愈合很重要[8]。在炎症过程中,M1和M2巨噬细胞之间存在动态平衡,炎症的初期阶段,M1巨噬细胞占主导地位,帮助抵抗感染并清除病原体,随着炎症的演变,M2巨噬细胞变得更为突出,帮助抑制炎症并促进愈合。细胞因子的微妙平衡是调节M1和M2巨噬细胞活动的关键。细胞因子如干扰素(interferon,IFN)和LPS倾向于推动M1巨噬细胞的激活,而IL-4和IL-13细胞因子则促进M2巨噬细胞的生成,炎症发生与M1和M2巨噬细胞失调有关[6]。

1.2 热应激诱导动物机体炎症发生的途径

热应激可通过激活炎症反应的2种主要信号通路激活炎症反应。其一,热应激通过激活MAPK与AP-1信号通路介导炎症反应。暴露于热应激会增加p38和细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)的磷酸化,并通过溶血磷脂酸(lysophosphatidic acid,LPA)受体激活G蛋白,活化的G蛋白通过MAPK信号通路增加NLRP3等炎症因子的表达,激活的炎症信号也会增加炎症细胞因子如IL-6和IL-18的分泌[9]。此外,热应激通过AP-1通路激活了猪半腱肌肌肉中的炎症信号传导,并提前激活了NF-κB通路[10]。其二,热应激通过LPS活化NF-κB途径与TLRs介导炎症反应。热应激可扰乱机体肠道菌群的微生态平衡,引起细菌易位,从而诱发炎症发生。这些LPS可以激活Toll样受体4(Toll-like receptor 4,TLR4)介导的反应,包括NF-κB和MAPK途径的启动。TLR4的信号传导启动细胞内信号级联,激活转录因子NF-κB,启动炎症基因的表达,产生IL-1、IL-4、IL-6、TNF-α和其他细胞因子,诱导免疫应答[11⇓-13]。
热应激通过激活瞬时受体电位(transient receptor potential,TRP)离子通道影响钙离子(Ca2+)内流,激活NF-κB诱导炎症的发生。TRP是广泛分布于细胞膜或细胞器膜上的Ca2+通道。瞬时受体电位亚家族V成员4(TRPV4)对温度敏感,可被高温激活[14]。激活的TRPV4通过影响Ca2+内流调节病理变化,包括炎症反应[15]。相关研究表明,Ca2+信号对于NF-κB的核易位至关重要[16-17]。胞内Ca2+浓度的升高会激活NF-κB[18]。此外,激活的TRPV4能介导LPS促炎细胞因子的释放[19]。在最新的一项研究中表明,热应激诱导了TRPV4的表达,LPS显著促进Ca2+内流,提示热应激可能通过激活TRPV4的表达介导Ca2+内流从而激活NF-κB,诱导肉鸡空肠的炎症[20]。
热应激可能通过诱导热休克蛋白(heat shock protein,HSP)的表达激活介导炎症的发生。有相关研究表明,在巨噬细胞中HSP70、HSP90刺激巨噬细胞分泌IL-1β和IL-12[21];在单核细胞中HSP70与质膜结合,引发细胞内钙快速通量,激活NF-κB,并上调TNF-α、IL-1β和IL-6的表达[22];在小胶质细胞中HSP60通过提高NLRP3在RNA和蛋白水平上的表达来进一步激活NLRP3炎症小体。此外,HSP60增强半胱天冬酶-1(Caspase-1)活性并增加小胶质细胞分泌IL-1β。敲低HSP60可减少IL-1β诱导的IL-1β在体外和体内的产生[23];在免疫细胞中,HSP70与受体CD14的相互作用导致IκBα在其丝氨酸32(Ser32)上的磷酸化,导致其被蛋白酶体降解并释放功能性NF-κB,然后,NF-κB将易位到细胞核,并导致几种促炎因子的过表达[24]。在热应激下,HSP70表达增加,表明HSP70可能是刺激促炎因子的主要信号。此外,据报道称,肠道上皮内源性HSP与染色质相关蛋白——高迁移率族蛋白1结合时,TLRs通路被激活,TLRs通路的激活最终导致炎症反应[25]。但具体作用机制需进一步研究。

1.3 热应激诱导炎症损伤

热应激明显增强了肉鸡肝脏中IL-6、TNF-α、NF-κB p65、IκB及其磷酸化蛋白的表达,促进NLRP3的活化以及NLRP3、Caspase-1和IL-1β水平的升高,引起肝脏炎症[26]。MyD88基因在鸡脾热应激炎症反应中起重要调控作用,热应激上调脾脏MyD88、IL-1β、TNF-α、NF-κB和TLR4的表达,刺激炎症因子的释放,而MyD88过表达显著上调巨噬细胞HD11炎症因子IL-1β、TNF-α、IL-8、NF-κB和TLR4的表达水平,进一步增强炎症反应[27]。在另一项研究中表明,热应激通过激活大肠杆菌感染鸡十二指肠和回肠的TLR4-NF-κB通路,诱导炎症因子反应,促进炎症的发生[28]。此外,热应激可通过诱导NF-κB通路激活,促进促炎细胞因子IL-18、TNF-α、IKK-α和IFN-γ的表达,引发炎症,造成鸡卵巢和下丘脑发生病理变化[29-30]。在猪骨骼肌细胞中,NF-κB的活化因子IKK-α的蛋白丰度及细胞核中AP-1的蛋白丰度在热应激4 h后增加,NF-κB总蛋白丰度在热应激6 h后增加,IL-6蛋白丰度和Janus激酶(Janus kinase,JAK)/信号传导与转录激活因子(signal transducer and activator of transcription,STAT)通路的激活降低,这表明热应激通过AP-1通路和NF-κB通路的早期激活诱导了猪骨骼肌的炎症发生[10]。在小鼠中,热应激增加了肠道TNF-α水平,上调了炎症相关基因IL-10、TNF-α、IFN-γ、TLR4和NF-κB的表达[31]。在小鼠HL1心房肌细胞中,热应激提高了HL1心房肌细胞IL-1β、IL-6、TNF-α水平,诱导HL1心房肌细胞炎症损伤[32]。在最近的一项研究中表明,热应激提高了LPS诱导的IL-1β表达,并且当牛子宫内膜上皮细胞细胞暴露于热应激时,LPS诱导的IL-6的表达也增加,当用小干扰RNA(siRNA)敲低上述基因后,HSP1A1和热休克因子1(heat shock factor 1,HSF1)的表达降低;然而,HSP1A1或HSF1的敲除进一步增加了热应激介导的炎症介质表达增加,这表明热应激增加牛子宫内膜上皮细胞对LPS的炎症反应,而HSP1A1和HSF1有助于抑制炎症反应,提示热应激可能抑制HSP1A1和HSF1的表达介导牛子宫内膜上皮细胞炎症反应[33]。此外,热应激激活家畜的下丘脑-垂体-肾上腺轴,该轴在被激活时释放糖皮质激素,抑制细胞因子的合成和释放,破坏促炎因子和抗炎因子之间的平衡,引起炎症,由此导致畜禽的免疫力下降[34]。

2 热应激诱导细胞自噬的主要途径

2.1 细胞自噬

蛋白质的合成与降解间动态平衡是构成细胞内稳态的基础,其核心是蛋白质折叠和蛋白质降解之间的平衡,前者由热休克反应的细胞伴侣控制,后者由泛素蛋白酶体系统、自噬和其他溶酶体依赖系统控制。自噬主要有3种类型:伴侣介导的自噬、微自噬和巨自噬。巨自噬是自噬的主要过程,通常情况下,自噬指的是巨自噬。自噬涉及以下过程。首先,自噬液泡通过吞噬一部分细胞质或受损的细胞器形成自噬体的双膜或多膜[35-36];接下来,自噬体与溶酶体融合形成降解捕获物质的自噬体,并通过酶和活性氧(reactive oxygen species,ROS)、活性氮(reactive nitrogen species,RON)降解其内容物[37]。自噬由Unc-51样自噬激活激酶1(Unc-51-like autophagy-activating kinases 1,ULK1)复合物——酵母中的自噬相关蛋白(autophagy related,Atg)1启动,其磷酸化下游自噬蛋白[38-39]。跨膜结合的Atg9提供形成吞噬体的双膜,主要来自内质网。吞噬细胞膜的延伸是通过苄氯素1(Beclin 1)-磷脂酰肌醇3-磷酸激酶(phosphatidylinositol 3-phosphate kinase,PI3K)复合体产生磷脂酰肌醇3-磷酸(phosphatidylinositol 3-phosphate,PI3P),然后再招募WD重复结构域-磷酸肌醇相互作用复合体——酵母中的Atg2~Atg18[40-41]。

2.2 热应激通过热休克反应诱导自噬

自噬可以通过多种信号通路调节,但热应激诱导细胞自噬的信号通路相关研究比较少。热应激可引起许多细胞内变化,甚至可能导致细胞稳态的丧失。高温诱导的蛋白质变性和聚集是破坏细胞内稳态的关键。在分子水平上,它针对多种蛋白质,如细胞骨架结构、质膜组分、细胞内酶和信号转导分子[42]。热应激在HSP的分子伴侣的帮助下诱导热休克反应(heat shock response,HSR)机制,上调HSF1,HSF1是细胞稳态过程的主要参与者[43]。HSP在蛋白质保护和体内平衡中起着重要作用。在生理状态下,HSF1作为无活性的单体存在于细胞质中。热应激下,HSR机制被激活,HSF1单体转化为DNA结合同源三聚体,从细胞质转移到细胞核,与存在于热休克基因中的顺式作用DNA元件(称为热休克元件)结合,并激活热休克基因(如HSP27、HSP70和HSP90)的转录[43⇓-45]。过表达HSP70可以抑制自噬标志物轻链3(light chain 3,LC3)-Ⅱ蛋白的基础水平,从而抑制自噬的激活[46]。相关研究表明,HSF1可诱导细胞自噬,HSF1敲低或缺失可以提高自噬的基础水平[46],而组成型HSF1激活导致自噬减少[47]。据报道,HSF1的激活也会诱导抗凋亡蛋白——B细胞淋巴瘤-2(Bcl-2)相互作用细胞死亡抑制因子[BIS,也称为B细胞淋巴瘤-2关联永生基因(BAG)3]的表达,同时BAG3参与促进自噬[48]。BAG3是BAG辅助伴侣家族的成员,能促进自噬,受到HSF1的调控,在高温或者应激条件下被激活,但HSF1与BAG3间具体作用机制需进一步研究。
此外,热应激可造成内质网中未折叠或错误折叠蛋白增加,引发内质网应激。HSF1可诱导内质网中启动的未折叠蛋白反应(unfolded protein response,UPR)。UPR的过程依赖于3种主要的跨膜内质网传感器蛋白的激活,即蛋白激酶R样内质网激酶(protein kinase R-like endoplasmic reticulum kinase,PERK)、肌醇需要酶-1α(inositol-requiring enzyme-1α,IRE-1α)和激活转录因子(activating transcription factor,ATF)6。在内质网应激期间,当未折叠的多肽在内质网内变得丰富时,导致IRE-1α和ATF6协同作用,激活内质网伴侣基因增加蛋白质的折叠反应,如葡萄糖相关蛋白94(Grp94)、内质网蛋白72(Erp72)、葡萄糖相关蛋白78(Grp78)和亲环素B(CypB)[49-50]。此外,内质网中错误折叠蛋白的存在激活PERK,使真核翻译起始因子2α(eukaryotic initiation factor 2α,eIF2α)的α亚基磷酸化,抑制蛋白质合成,减少内质网的负担。PERK的激活可通过ATF4促进自噬。ATF4是一个转录因子,它能调控一系列与自噬相关的基因,包括Atg5和LC3等。但IRE-1α与ATF6如何具体与自噬相关联,需要进一步研究。自噬通过回收受损的蛋白质、清除错误折叠蛋白质协同UPR,并提供新的构建块来取代受损或耗尽的细胞成分。这一过程是通过诱导几种自噬基因启动的,如LC3、Beclin 1和其他Atg[51]。该过程对维持蛋白质稳态具有重要作用。

2.3 热应激通过氧化应激诱导自噬发生

热应激也可通过诱导ROS的生成来调节自噬,ROS可以以细胞类型和时间依赖的方式调节自噬。有研究表明,ROS作用于Beclin-1复合物和抗凋亡的B细胞淋巴瘤同源物如Bcl-2、B细胞淋巴瘤特大(B-cell lymphoma-extra large,Bcl-xL)和髓细胞白血病-1(myeloid leukemia-1,Mcl-1)[52],该复合物抑制Beclin-1促自噬活性[52-53],其被ROS解离激活Beclin-1,促进自噬。ROS还通过调节NF-κB活性诱导自噬,进而诱导Beclin-1表达[54-55]。此外,ROS还上调缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)的活性,从而促进自噬关键蛋白的转录,如B细胞淋巴瘤相互作用蛋白3(B-cell lymphoma-2 interacting protein 3,BNIP3)和通过Beclin-1调节自噬的NIP样蛋白X(NIX)的表达[56]。另一个参与高温诱导氧化应激的防御分子是核因子E2相关因子2(nuclear factor E2-related factor 2,Nrf2)。在生理条件下,Nrf2以无活性形式与Kelch样ECH相关蛋白1(Kelch-like ECH-associated protein 1,Keap1)一起存在于细胞质中。Nrf2调控通过p62与自噬相关,p62是自噬底物和货物受体。p62也被称为SQSMT1,将靶蛋白转移到自噬体进行降解[57]。在高温诱导氧化应激反应中,p62磷酸化增加了其与Keap1的结合亲和力,结合解离Nrf2-Keap1复合物,导致Nrf2的释放[58]。Keap1和p62复合体在自噬过程中被快速降解,而Nrf2易位进入细胞核,激活多种抗氧化剂和自噬基因如Atg3、Atg5、Atg7和SQSMT1的表达[57-58]。

2.4 热应激通过单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)相关通路诱导自噬

热应激通过ATP-AMPK-哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路诱导细胞自噬。mTOR是一种调节细胞生长和存活的蛋白激酶,调节蛋白质、脂质和核苷酸的合成,是自噬起始的关键调节因子。热应激降低ATP水平,随着ATP水平的降低,由于腺苷酸激酶平衡,二磷酸腺苷(ADP)浓度的提高,导致单磷酸腺苷(AMP)浓度升高、AMP/ATP值升高,AMP/ATP通过苏氨酸172(Thr172)位点磷酸化直接激活AMPK,AMPK的激活抑制mTORC1活性并通过ULK1和Atg13的去磷酸化促进自噬,防止热处理引发的细胞凋亡,这是自噬启动复合物的2个关键组成部分[56,58⇓-60]。这种去磷酸化导致Beclin-1/磷脂酰肌醇-3激酶Ⅲ复合物的激活增强自噬[61]。
综上可知,热应激激活HSR机制诱导细胞自噬,缓解热应激造成的内质网应激并回收利用受损蛋白质维持蛋白质稳态;通过诱导ROS的生成介导NF-κB通路并诱发氧化应激通过Nrf2相关通路诱导自噬;通过ATP-AMPK-mTOR信号通路诱导细胞自噬,维持能量平衡,从而缓解热应激诱导的细胞凋亡。

3 热应激诱导的炎症和自噬间的相互作用

热应激可诱导动物机体多种炎症的发生,炎症和自噬通路之间存在复杂的相互作用。一方面,炎症反应可抑制细胞自噬;而另一方面,自噬通过降解炎症因子和调解因子参与负反馈调控炎症反应。NF-κB是炎症的关键激活因子,通过诱导IL-1β前体(pro-IL-1β)和NLRP3的表达,启动NLRP3炎症小体的激活。NLRP3炎症小体是胞质多蛋白复合物,可响应PAMPs和DAMPs诱导炎症和细胞死亡,识别PAMPs或DAMPs导致炎症小体复合物的形成,导致Caspase-1的激活,随后裂解和释放促炎细胞因子,诱发细胞凋亡抑制自噬。此外,炎症小体的激活导致巨噬细胞中快速的Caspase-1依赖性线粒体自噬阻滞,从而导致线粒体DNA(mtDNA)的积累和线粒体功能失调。在炎症小体激活后,Caspase-1介导的帕金蛋白(Parkin)的裂解有助于骨髓源性巨噬细胞中Caspase-1依赖性的线粒体自噬阻滞,这导致mtDNA的积累和线粒体功能障碍,而在表达抗裂解Parkin的细胞中,线粒体功能障碍被减弱,累积的受损线粒体会产生更多的mROS,从而进一步抑制自噬并激活巨噬细胞中的炎性小体和炎症性热噬细胞死亡,并放大炎症反应[62]。
过度炎症可导致器官和组织损伤和炎症性疾病,自噬可通过去除NLRP3炎症小体激活剂和炎症成分来抑制炎症反应。NF-κB p62诱导自噬通路是巨噬细胞内在调节回路,NF-κB通过该途径协调NLRP3炎性小体的激活和细胞因子的释放,从而将巨噬细胞介导的免疫集中在消除感染因子上,同时防止因过度IL-1β分泌和炎症性巨噬细胞死亡导致的长期组织炎症和损伤[63]。此外,M1和M2巨噬细胞极化的平衡参与了炎症的调节。研究表明,AMPK/Nrf2信号及其下游血红素氧合酶-1(heme oxygenase-1,HO-1)具有抗炎作用,并促进巨噬细胞向M2表型极化[64-65]。最近一项研究表明,Nrf2过表达抑制M1巨噬细胞极化,改善自噬,促进M2巨噬细胞极化,Nrf2过表达促进LPS诱导的LC3-Ⅱ/LC3-Ⅰ和Beclin1上调以及p62下调,Nrf2过表达抑制LPS/IFN-γ诱导的诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)、IL-6、IL-1β和TNF-α的上调,并在mRNA水平上促进IL-4/IL-13诱导的Arg1、Fizz1、Ym1和IL-10的上调[66]。因此,炎症小体可激活Nrf2通路促进M2巨噬细胞极化,并促进细胞自噬抑制炎症因子的表达负反馈调控炎症。另外,自噬在维持肠道内稳态、调节肠道菌群与先天免疫和适应性免疫的相互作用以及宿主对肠道病原体的防御中起着关键作用[67]。肠上皮屏障的完整性、肠道菌群的调控受到自噬的调控[68-69]。内质网应激是限制黏液分泌的细胞内在开关,自噬通过缓解内质网应激来维持肠道稳态,而肠道菌群及其代谢产物通过mTOR通路调节宿主的各种生理功能,维持体内稳态[69-70]。肠道炎症发生通过相关信号通路诱导细胞自噬缓解炎症损伤,自噬缺陷或自噬抑制会加重炎症损伤。在猪肠道上皮细胞中,用促炎细胞因子肿瘤坏死因子处理后,自噬介导的封闭蛋白2(CLDN2)降解受到抑制,肠上皮Caco-2单层细胞CLDN2水平升高和紧密连接部分缺陷[71]。
综上所述,热应激诱导的炎症可抑制细胞自噬水平放大炎症反应,而自噬通过降解炎症因子和调解因子参与负反馈调控炎症反应,热应激诱导的炎症与自噬间存在相互作用,因此增强自噬水平可缓解炎症损伤。

4 营养手段对自噬水平的调控

白藜芦醇是多种植物中的多酚化合物,具有抗氧化、抗炎和免疫调节特性。最近的一项研究表明,在肉鸡中添加400 mg/kg白藜芦醇,与热应激组相比,其提高了肺脏中Beclin-1和LC3-Ⅱ基因的表达以及LC3-B蛋白的水平,抑制了LC3-Ⅰ和p62基因的表达[72],表明白藜芦醇可增强自噬水平。辅酶Q10,也称为泛醌,是一种内源性合成的辅助因子,具有抗氧化能力。热应激期间用辅酶Q10处理原代鸡心肌细胞后,增加了自噬体的形成,增强了LC3-Ⅱ、Atg05、Beclin-1蛋白的表达,降低了p62蛋白的表达[73]。在地塞米松诱导氧化应激下,在肉鸡饲粮中添加500 mg/kg绿原酸,提高了LC3-Ⅰ、LC3-Ⅱ、Beclin-1和Atg7 mRNA的表达,降低了p62蛋白的表达[74]。乙酰左旋肉碱是线粒体能量代谢的有效底物,在脂肪酸的氧化中起着至关重要的作用。小鼠精原细胞GC-1在42 ℃下孵育90 min后经150 μmol/L乙酰左旋肉碱处理,有效促进了GC-1细胞中Beclin-1和LC3-Ⅱ的mRNA和蛋白表达水平,提高了LC3-Ⅱ的平均光密度(AOD)和溶酶体生物发生相关基因[Mcoln1、溶酶体相关膜蛋白(LAMP)1和LAMP2]的表达,但降低了热应激下p62的蛋白水平[75]。总之,可通过添加一定量的营养性添加剂增强自噬水平缓解应激,但相关研究较少,需进一步研究。

5 小结

热应激通过相关通路诱导动物机体炎症反应及自噬,炎症的发生损伤组织器官,自噬通过降解炎症因子和调解因子参与负反馈调控炎症反应,但过度炎症抑制自噬放大炎症反应。热应激诱导的自噬与自噬间存在相互作用。通过营养性添加剂处理,可增强自噬水平缓解热应激,但相关研究较少,需进一步研究。

参考文献

原文顺序 | 文献年度倒序 | 文中引用次数倒序
[1]
BIASIZZO M, KOPITAR-JERALA N. Interplay between NLRP3 inflammasome and autophagy[J]. Frontiers in Immunology, 2020,11:591803.

[2]
CHEN R H, CHEN Y H, HUANG T Y. Ubiquitin-mediated regulation of autophagy[J]. Journal of Biomedical Science, 2019, 26(1):80.

[3]
TAKAHAMA M, AKIRA S, SAITOH T. Autophagy limits activation of the inflammasomes[J]. Immunological Reviews, 2018, 281(1):62-73.

DOI PMID

[4]
LIU T, ZHANG L Y, JOO D, et al. NF-κB signaling in inflammation[J]. Signal Transduction and Targeted Theapy, 2017,2:17023.

[5]
THALHAMER T, MCGRATH M A, HARNETT M M. MAPKs and their relevance to arthritis and inflammation[J]. Rheumatology(Oxford,England), 2008, 47(4):409-414.

[6]
WANG N, LIANG H W, ZEN K. Molecular mechanisms that influence the macrophage M1-M2 polarization balance[J]. Frontiers in Immunology, 2014,5:614.

[7]
SICA A, MANTOVANI A. Macrophage plasticity and polarization:in vivo veritas[J]. The Journal of Clinical Investigation, 2012, 122(3):787-795.

[8]
MOSSER D M. The many faces of macrophage activation[J]. Journal of Leukocyte Biology, 2003, 73(2):209-212.

DOI PMID

[9]
CHEI S, SONG J H, OH H J, et al. Gintonin-enriched fraction suppresses heat stress-induced inflammation through LPA receptor[J]. Molecules, 2020, 25(5):1019.

[10]
GANESAN S, VOLODINA O, PEARCE S C, et al. Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle[J]. Physiological Reports, 2017, 5(16):e13397.

[11]
KAWAI T, AKIRA S. The role of pattern-recognition receptors in innate immunity:update on Toll-like receptors[J]. Nature Immunology, 2010, 11(5):373-384.

[12]
NAWAB A, AN L L, WU J, et al. Chicken Toll-like receptors and their significance in immune response and disease resistance[J]. International Reviews of Immunology, 2019, 38(6):284-306.

DOI PMID

[13]
VIDYA M K, KUMAR V G, SEJIAN V, et al. Toll-like receptors:significance,ligands,signaling pathways,and functions in mammals[J]. International Reviews of Immunology, 2018, 37(1):20-36.

[14]
SHIBASAKI K, SUGIO S, TAKAO K, et al. TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior[J]. Pflugers Archiv:European Journal of Physiology, 2015, 467(12):2495-2507.

[15]
WANG Z Q, ZHOU L, AN D, et al. TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice[J]. Cell Death & Disease, 2019, 10(6):386.

[16]
D’ALDEBERT E, CENAC N, ROUSSET P, et al. Transient receptor potential vanilloid 4 activated inflammatory signals by intestinal epithelial cells and colitis in mice[J]. Gastroenterology, 2011, 140(1):275-285.

DOI PMID

[17]
SCHAPPE M S, SZTEYN K, STREMSKA M E, et al. Chanzyme TRPM7 mediates the Ca2+ influx essential for lipopolysaccharide-induced Toll-like receptor 4 endocytosis and macrophage activation[J]. Immunity, 2018, 48(1):59-74.e5.

[18]
DOLMETSCH R E, LEWIS R S, GOODNOW C C, et al. Differential activation of transcription factors induced by Ca2+ response amplitude and duration[J]. Nature, 1997, 386(6627):855-858.

[19]
LI W, XU Y, LIU Z H, et al. TRPV4 inhibitor HC067047 produces antidepressant-like effect in LPS-induced depression mouse model[J]. Neuropharmacology, 2021,201:108834.

[20]
XU P, LIN H, JIAO H C, et al. Chicken embryo thermal manipulation alleviates postnatal heat stress-induced jejunal inflammation by inhibiting transient receptor potential V4[J]. Ecotoxicology and Environmental Safety, 2023,256:114851.

[21]
BASU S, BINDER R J, SUTO R, et al. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway[J]. International Immunology, 2000, 12(11):1539-1546.

DOI PMID

[22]
ASEA A, KRAEFT S K, KURT-JONES E A, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway,demonstrating its dual role as a chaperone and cytokine[J]. Nature Medicine, 2000, 6(4):435-442.

[23]
SWAROOP S, MAHADEVAN A, SHANKAR S K, et al. Correction to:HSP60 critically regulates endogenous IL-1β production in activated microglia by stimulating NLRP3 inflammasome pathway[J]. Journal of Neuroinflammation, 2018, 15(1):317.

[24]
MARTINE P, RÉBÉ C. Heat shock proteins and inflammasomes[J]. International Journal of Molecular Sciences, 2019, 20(18):4508.

[25]
SCAFFIDI P, MISTELI T, BIANCHI M E. Erratum:release of chromatin protein HMGB1 by necrotic cells triggers inflammation[J]. Nature, 2010, 467(7315):622.

[26]
LIU Y L, DING K N, SHEN X L, et al. Chronic heat stress promotes liver inflammation in broilers via enhancing NF-κB and NLRP3 signaling pathway[J]. BMC Veterinary Research, 2022, 18(1):289.

[27]
DING M X, YU Y G, ZHU Z Y, et al. Regulation of the MyD88 gene in chicken spleen inflammation induced by stress[J]. Journal of Animal Science, 2023,101:skad060.

[28]
TANG L P, LI W H, LIU Y L, et al. Heat stress aggravates intestinal inflammation through TLR4-NF-κB signaling pathway in Ma chickens infected with Escherichia coli O157:H7[J]. Poultry Science, 2021, 100(5):101030.

[29]
CAO X H, GUO L Y, ZHOU C M, et al. Effects of N-acetyl-L-cysteine on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets[J]. Poultry Science, 2023, 102(1):102274.

[30]
ZHAO Y L, ZHUANG Y, SHI Y, et al. Effects of N-acetyl-L-cysteine on heat stress-induced oxidative stress and inflammation in the hypothalamus of hens[J]. Journal of Thermal Biology, 2021,98:102927.

[31]
LU R H, HU J H, LIU X X, et al. Mogroside-rich extract from Siraitia grosvenorii fruits protects against heat stress-induced intestinal damage by ameliorating oxidative stress and inflammation in mice[J]. Food & Function, 2023, 14(2):1238-1247.

[32]
赵海玉, 谭振林, 何利伟, 等. 胺碘酮促进小鼠HL1心房肌细胞热处理诱导的凋亡、炎症及氧化应激[J]. 南方医科大学学报, 2021, 41(3):406-411.

DOI

ZHAO H Y, TAN Z L, HE L W, et al. Amiodarone promotes heat-induced apoptosis,inflammation and oxidative stress in mouse HL1 atrial myocytes[J]. Journal of Southern Medical University, 2021, 41(3):406-411. (in Chinese)

[33]
MOLINARI P C C, BROMFIELD J J. Inflammatory responses of bovine endometrial epithelial cells are increased under in vitro heat stress conditions[J]. Journal of Thermal Biology, 2023,114:103564.

[34]
BAGATH M, KRISHNAN G, DEVARAJ C, et al. The impact of heat stress on the immune system in dairy cattle:a review[J]. Research in Veterinary Science, 2019,126:94-102.

[35]
MIZUSHIMA N, YOSHIMORI T, OHSUMI Y. The role of Atg proteins in autophagosome formation[J]. Annual Review of Cell and Developmental Biology, 2011,27:107-132.

[36]
PARZYCH K R, KLIONSKY D J. An overview of autophagy:morphology,mechanism,and regulation[J]. Antioxidants & Redox Signaling, 2014, 20(3):460-473.

[37]
MIZUSHIMA N. A brief history of autophagy from cell biology to physiology and disease[J]. Nature Cell Biology, 2018, 20(5):521-527.

DOI PMID

[38]
ITAKURA E, MIZUSHIMA N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins[J]. Autophagy, 2010, 6(6):764-776.

DOI PMID

[39]
ZACHARI M, GANLEY I G. The mammalian ULK1 complex and autophagy initiation[J]. Essays in Biochemistry, 2017, 61(6):585-596.

DOI PMID

[40]
KISHI-ITAKURA C, KOYAMA-HONDA I, ITAKURA E, et al. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells[J]. Journal of Cell Science, 2014, 127(Pt 18):4089-4102.

[41]
LEVINE B, KROEMER G. Biological functions of autophagy genes:a disease perspective[J]. Cell, 2019, 176(1/2):11-42.

[42]
KAUR P, ALIRU M L, CHADHA A S, et al. Hyperthermia using nanoparticles—promises and pitfalls[J]. International Journal of Hyperthermia, 2016, 32(1):76-88.

[43]
TABUCHI Y, KONDO T. Targeting heat shock transcription factor 1 for novel hyperthermia therapy (review)[J]. International Journal of Molecular Medicine, 2013, 32(1):3-8.

DOI PMID

[44]
WANG A A, CHEN M J, ZHOU J, et al. HSP27,70 and 90,anti-apoptotic proteins,in clinical cancer therapy (review)[J]. International Journal of Oncology, 2014, 45(1):18-30.

[45]
XIA Y, ROCCHI P, IOVANNA J L, et al. Targeting heat shock response pathways to treat pancreatic cancer[J]. Drug Discovery Today, 2012, 17(1/2):35-43.

[46]
DOKLADNY K, ZUHL M N, MANDELL M, et al. Regulatory coordination between two major intracellular homeostatic systems:heat shock response and autophagy[J]. The Journal of Biological Chemistry, 2013, 288(21):14959-14972.

[47]
ZHAO Y B, GONG S F, SHUNMEI E, et al. Induction of macroautophagy by heat[J]. Molecular Biology Reports, 2009, 36(8):2323-2327.

DOI PMID

[48]
NGUYEN H A, KIM S A. 2'-hydroxycinnamaldehyde induces apoptosis through HSF1-mediated BAG3 expression[J]. International Journal of Oncology, 2017, 50(1):283-289.

[49]
REMONDELLI P, RENNA M. The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance[J]. Frontiers in Molecular Neuroscience, 2017,10:187.

[50]
DEVASTHANAM A S, TOMASI T B. Dicer protein levels elevated by mild hyperthermia promote a pro-survival phenotype[J]. Oncotarget, 2017, 8(40):67001-67016.

DOI PMID

[51]
LI S, ZHOU Y, FAN J J, et al. Heat shock protein 72 enhances autophagy as a protective mechanism in lipopolysaccharide-induced peritonitis in rats[J]. The American Journal Pathology, 2011, 179(6):2822-2834.

[52]
WU Y B, PAN M X, CUI S Z, et al. Autophagic death induced by thermo-chemotherapy in gastric cancer cells results from the reactive oxygen species pathway[J]. Molecular Medicine Reports, 2016, 14(2):1210-1218.

[53]
GIBSON S B. Investigating the role of reactive oxygen species in regulating autophagy[J]. Methods in Enzymology, 2013,528:217-235.

[54]
JIANG Q, WANG Y H, LI T J, et al. Heat shock protein 90-mediated inactivation of nuclear factor-κB switches autophagy to apoptosis through BECN1 transcriptional inhibition in selenite-induced NB4 cells[J]. Molecular Biology of the Cell, 2011, 22(8):1167-1180.

DOI PMID

[55]
BOYER-GUITTAUT M, POILLET L, LIANG Q L, et al. The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells[J]. Autophagy, 2014, 10(6):986-1003.

[56]
CICCARONE F, CASTELLI S, CIRIOLO M R. Oxidative stress-driven autophagy acROSs onset and therapeutic outcome in hepatocellular carcinoma[J]. Oxidative Medicine and Cellular Longevity, 2019,2019:6050123.

[57]
LIU W J, YE L, HUANG W F, et al. p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation[J]. Cellular & Molecular Biology Letters, 2016,21:29.

[58]
KAPUY O, PAPP D, VELLAI T, et al. Systems-level feedbacks of NRF2 controlling autophagy upon oxidative stress response[J]. Antioxidants(Basel,Switzerland), 2018, 7(3):39.

[59]
JIANG J Y, CHEN S H, LI K, et al. Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma[J]. International Journal of Hyperthermia, 2019, 36(1):499-510.

DOI PMID

[60]
SU K H, DAI C K. mTORC1 senses stresses:coupling stress to proteostasis[J]. BioEssays, 2017, 39(5):10.

[61]
ZHANG Y, CALDERWOOD S K. Autophagy, protein aggregation and hyperthermia:a mini-review[J]. International Journal of Hyperthermia, 2011, 27(5):409-414.

[62]
YU J J, NAGASU H J E, MURAKAMI T, et al. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy[J]. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(43):15514-15519.

DOI PMID

[63]
ZHONG Z Y, UMEMURA A, SANCHEZ-LOPEZ E, et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria[J]. Cell, 2016, 164(5):896-910.

DOI PMID

[64]
WANG Y J, HUANG Y, XU Y Z, et al. A dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization[J]. Antioxidants & Redox Signaling, 2018, 28(2):141-163.

[65]
HAN R R, XIAO J T, ZHAI H, et al. Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages[J]. Journal of Neuroinflammation, 2016, 13(1):97.

DOI PMID

[66]
LUO J, WANG J, ZHANG J, et al. Nrf2 deficiency exacerbated CLP-induced pulmonary injury and inflammation through autophagy- and NF-κB/PPARγ-mediated macrophage polarization[J]. Cells, 2022, 11(23):3927.

[67]
ELSHAER D, BEGUN J. The role of barrier function,autophagy,and cytokines in maintaining intestinal homeostasis[J]. Seminars in Cell & Developmental Biology, 2017,61:51-59.

[68]
FENG Y H, WANG Y, WANG P, et al. Short-chain fatty acids manifest stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 inflammasome and autophagy[J]. Cellular Physiology and Biochemistry, 2018, 49(1):190-205.

DOI PMID

[69]
NOURELDEIN M H, EID A A. Gut microbiota and mTOR signaling:insight on a new pathophysiological interaction[J]. Microbial Pathogenesis, 2018,118:98-104.

[70]
NAAMA M, TELPAZ S, AWAD A, et al. Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress[J]. Cell Host & Microbe, 2023, 31(3):433-446.e4.

[71]
ZHANG C, YAN J K, XIAO Y T, et al. Inhibition of autophagic degradation process contributes to claudin-2 expression increase and epithelial tight junction dysfunction in TNF-α treated cell monolayers[J]. International Journal of Molecular Sciences, 2017, 18(1):157.

[72]
LU M H, DING K N, LIANG S S, et al. Resveratrol inhibits oxidative damage in lungs of heat-stressed broilers by activating Nrf2 signaling pathway and autophagy[J]. Ecotoxicology and Environmental Safety, 2023,258:114949.

[73]
XU J, HUANG B, TANG S, et al. Co-enzyme Q10 protects primary chicken myocardial cells from heat stress by upregulating autophagy and suppressing the PI3K/AKT/mTOR pathway[J]. Cell Stress & Chaperones, 2019, 24(6):1067-1078.

[74]
LIU H W, LI X M, SHI S Y, et al. Chlorogenic acid improves growth performance and intestinal health through autophagy-mediated nuclear factor erythroid 2-related factor 2 pathway in oxidatively stressed broilers induced by dexamethasone[J]. Poultry Science, 2022, 101(9):102036.

[75]
QIAO N, CHEN H M, DU P Q, et al. Acetyl-L-carnitine induces autophagy to promote mouse spermatogonia cell recovery after heat stress damage[J]. BioMed Research International, 2021,2021:8871328.

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