动物营养学报    2019, Vol. 31 Issue (10): 4421-4426    PDF    
组蛋白去乙酰化酶调控肠道抗菌肽表达的研究进展
易宏波 , 王丽 , 熊云霞 , 蒋宗勇     
广东省农业科学院动物科学研究所, 农业部华南动物营养与饲料重点实验室, 国家畜禽育种重点实验室, 广东省动物育种与营养公共实验室, 广东省畜禽育种与营养研究重点实验室, 广州 510640
摘要: 抗菌肽具有抗菌、免疫调节、改善肠道黏膜屏障等功能。断奶仔猪免疫力低下,抗菌肽在其肠道上皮抵抗病原菌入侵中发挥关键作用。然而,有效提升抗菌肽表达且不引发肠道炎症成为了营养调控仔猪肠道免疫力的研究难点。组蛋白去乙酰化酶(HDAC)抑制剂通过调节抗菌肽启动子区域组蛋白修饰,从而精准提升肠道抗菌肽表达。因此,HDAC成为营养调控肠道抗菌肽表达的重要靶点。本文就抗菌肽的生物学功能及组蛋白修饰与HDAC调控肠道抗菌肽表达的作用进行了综述,并总结了营养物质通过HDAC促进肠道抗菌肽表达的可能机制,以期为营养调控肠道抗菌肽表达、提升断奶仔猪肠道免疫力提供理论指导。
关键词: 抗菌肽    组蛋白去乙酰化酶    组蛋白修饰    肠道免疫    断奶仔猪    
Research Advance on Antimicrobial Peptide Expression Regulated by Histone Deacetylase in Intestines
YI Hongbo , WANG Li , XIONG Yunxia , JIANG Zongyong     
State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed Science in South China Ministry of Agriculture, Guangdong Public Laboratory of Animal Breeding and Nutrition, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
Abstract: Antimicrobial peptides (AMPs) showed functions of antibacterial activity, immunomodulation and improving intestinal mucosal barriers. Given low intestinal immunity of weaned piglets, AMPs play key roles in the intestinal epithelium against pathogens invasion. However, it is difficulty to effectively improve the AMPs expression and not to cause intestinal inflammation during nutritional regulation of intestinal immunity in weaned piglets. Histone deacetylase (HDAC) inhibitors precisely enhanced the AMPs expression by modulating histone modifications in the promoter region of the AMPs genes. Therefore, HDAC were important targets for the regulation of intestinal AMPs expression. In this paper, we reviewed the biological functions of AMPs, and mechanisms of AMPs expression regulated by histone modification and HDAC. In addition, we summarized possible mechanisms of AMPs expression regulated by nutrients via HDAC. The aim of this paper is to provide theoretical guidance for nutritional regulation of AMPs expression and improvement of intestinal immunity in weaned piglets.
Key words: antimicrobial peptide    histone deacetylase    histone modification    intestinal immunity    weaned piglets    

抗菌肽是一类重要的固有免疫因子,具有抗菌、免疫调节、改善肠道黏膜屏障等功能[1-2]。断奶仔猪肠道适应性免疫系统发育尚不成熟,抗菌肽在其肠道黏膜抗细菌感染中发挥重要作用。营养调控抗菌肽表达是增强断奶仔猪肠道免疫力的有效措施,然而,生产实践中发现在增强肠道抗菌肽表达时,促炎症因子表达也升高,易引发仔猪肠道炎症,导致产品使用效果不稳定。因此,如何有效增强抗菌肽表达且不引发肠道炎症成为了营养调控肠道抗菌肽表达的研究难点。组蛋白修饰是精准调控抗菌肽表达的重要方式,而组蛋白去乙酰化酶(histone deacetylase,HDAC)是营养调控组蛋白修饰的重要途径[3-4]。Fischer等[3]研究表明,HDAC抑制剂通过调节组蛋白修饰,显著提高肠道上皮抗菌肽表达,但不影响促炎因子表达。研究发现,丁酸等营养物质提高肠道上皮抗菌肽表达,与HDAC密切相关[4-5]。HDAC成为营养调控肠道抗菌肽表达的关键靶点。因此,本文重点综述了组蛋白修饰与HDAC在肠道抗菌肽表达调控中的作用,并总结了HDAC介导营养物质调控肠道抗菌肽表达的可能机制,以期为营养精准调控断奶仔猪肠道抗菌肽表达提供理论依据。

1 抗菌肽的生物学功能及其在仔猪肠道上皮的作用

抗菌肽,又称宿主防御肽,是一类由基因编码的多肽类小分子物质,一般包含12~50个氨基酸残基,带正电荷,呈两亲性分子结构,是重要的固有免疫因子[6]。抗菌肽通过破坏细胞膜而杀灭细菌,不易产生耐药性,受到广泛关注。近年来研究发现,抗菌肽除了杀菌活性,还发挥趋化免疫细胞、缓解肠道炎症反应等免疫调控功能[7-8]。抗菌肽通过类甲酰肽受体1(formyl peptide receptor like-1,FPRL1)和类甲酰肽受体2(formyl peptide receptor like-2,FPRL2)介导从而趋化中性粒细胞、单核细胞、巨噬细胞、树突状细胞等免疫细胞,共同发挥抗感染作用[7]。同时,抗菌肽通过以下5种方式抑制肠道炎症反应:1)直接中和细菌脂多糖;2)阻断髓样分化因子88(myeloid differentiation factor 88,MyD88)和丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路;3)抑制核因子-κB(nuclear factor-kappa B,NF-κB)蛋白的移位;4)通过激活MAPK和磷脂酰肌醇3-激酶(phosphoinositide 3-kinase,PI3K)通路选择性提高抑炎因子表达;5)直接影响促炎因子的翻译、稳定性或者加工过程[2, 8]。此外,抗菌肽还能通过增强肠道上皮屏障功能来提高机体对病原菌感染的抵抗能力。例如,抗菌肽C-BF和LFP-20能够提高肠道紧密连接蛋白表达,缓解紧密连接结构损伤,保护肠道物理屏障功能[9-10]。Tokumaru等[11]研究发现,抗菌肽LL-37可以激活MAPK、PI3K等信号通路,进而激活表皮生长因子受体和FPRL1的表达,从而改善上皮细胞修复功能。因此,抗菌肽具有抗菌、免疫调节、改善肠道上皮屏障等功能,在肠道上皮抗病原菌感染中发挥关键作用。

刚断奶的仔猪免疫力低下,肠道适应性免疫系统发育尚不成熟,抗菌肽是影响其肠道上皮细胞抵抗细菌感染的关键因素。仔猪肠道上皮细胞分泌的抗菌肽主要包括猪源β-防御素(pBD,如pBD1、pBD2、pBD3等)和猪源Cathelicidins抗菌肽(PR39、PG1-5、PMAPs等),其中以pBD2和抗菌肽PR39最具代表性。研究发现,抗菌肽能够缓解腹泻仔猪和染菌猪肠上皮细胞的上皮屏障损伤[12-13]。仔猪断奶后前3 d采食量低,肠道上皮抗菌肽表达显著降低,易发生肠道炎症[14],这可能是仔猪断奶后第4~7天极易发生严重腹泻的原因。提高肠道抗菌肽表达是增强断奶仔猪肠道免疫力的有效措施。然而,抗菌肽与促炎因子存在同步表达,提高抗菌肽表达时易引起促炎因子大量表达,导致仔猪肠道炎症,造成产品使用效果不稳定。因此,如何有效提高肠道抗菌肽表达且不诱发肠道炎症成为了研究难点。

2 组蛋白乙酰化状态控制肠道抗菌肽表达

肠道上皮细胞通过多种信号通路维持宿主免疫反应与肠道微生物之间的动态平衡。然而,同一个信号通路控制上百个不同基因表达,这些基因表达的调控需要基因特异性而不是信号通路特异性,这种基因特异性调控途径依赖于固有免疫进化过程中形成的表观遗传学修饰方式[15-16]。组蛋白修饰是重要的表观遗传学修饰,精准调控固有免疫反应和相应防御基因的表达[17]。组蛋白修饰主要包括乙酰化/去乙酰化、甲基化/去甲基化、泛素化/去泛素化、磷酸化等。在组蛋白修饰方式中,组蛋白甲基化对抗菌肽表达无明显影响,而组蛋白乙酰化对抗菌肽转录调控发挥关键作用[3]。组蛋白的乙酰化状态由组蛋白乙酰基转移酶(histone acetyltransferase,HAT)和HDAC共同控制。HAT将乙酰基转移至组蛋白N端赖氨酸残基上,而HDAC去除赖氨酸残基上的乙酰基,组蛋白乙酰化使染色质结构打开,利于转录因子与转录位点的结合,促进基因转录表达。HAT和HDAC在调控基因表达的过程中保持动态平衡,避免基因表达异常。HDAC升高抑制基因转录表达,而抑制HDAC则促进基因转录表达。研究发现,HDAC是营养调控组蛋白修饰促进肠道抗菌肽表达的重要靶点[4-5]

3 HDAC抑制剂促进肠道抗菌肽表达

Fischer等[3]研究表明,HDAC抑制剂曲古抑菌素A(trichostatin A,TSA)和辛二酰苯胺异羟肟酸(suberoylannilide hydroxamic acid,SAHA)显著提高肠道上皮细胞抗菌肽HBD2和LL-37表达,但是不影响甚至降低白细胞介素-8(IL-8)、白细胞介素-1β(IL-1β)等炎症因子表达。转录因子进入染色质结合固有免疫基因的启动子,需要组蛋白H3、H4的赖氨酸残基乙酰化和组蛋白H3丝氨酸10磷酸化(pH3S10)[18]。HDAC抑制剂TSA增加组蛋白pH3S10表达水平,提高组蛋白H3第9赖氨酸(H3K9)、组蛋白H3第27赖氨酸(H3K27)、组蛋白H3第56赖氨酸(H3K56)等赖氨酸残基位点的乙酰化水平[3]。启动子区域组蛋白乙酰化组蛋白H3第9赖氨酸(acH3K9)、乙酰化组蛋白H3第27赖氨酸(acH3K27)、乙酰化组蛋白H3第56赖氨酸(acH3K56)、pH3S10水平升高是抗菌肽转录激活的典型标志。Fischer等[3]研究发现,HDAC抑制剂TSA提高抗菌肽HBD2启动子区域pH3S10、乙酰化NF-κB及组蛋白乙酰转移酶p300(p300)的蛋白表达,从而精准调控肠道上皮细胞抗菌肽HBD2表达,增强其抵抗细菌感染能力。TSA通过激活IκB激酶(inhibitor of NF-κB kinase,IKK)复合体促进pH3S10,通过p300乙酰化NF-κB并促进其在抗菌肽启动子区域募集。Xiong等[4]研究表明,丁酸钠抑制猪巨噬细胞HDAC活性,提高抗菌肽启动子区域acH3K9表达水平,从而促进猪巨噬细胞抗菌肽(pBD2和PR39)的表达。Schulthess等[5]研究表明,丁酸通过抑制HDAC3提高acH3K27水平,促进抗菌肽(S100A8/A9/A12)表达,提升小鼠巨噬细胞清除细菌的能力。由此可知,抑制HDAC调节抗菌肽启动子区域组蛋白H3修饰方式(acH3K9、acH3K27、acH3K56、pH3S10等),可特异性地提高肠道抗菌肽表达,增强其抗细菌感染能力,而不影响促炎因子表达(图 1)。然而,不同类型HDAC在调控肠道抗菌肽表达中的作用还有待进一步研究。

HDAC:组蛋白去乙酰化酶histone deacetylase;NF-κB:核因子-κB nuclear factor-kappa B;IκBα:核因子κB抑制蛋白inhibitor of NF-κB;IKK:IκB激酶inhibitor of NF-κB kinase;H3:组蛋白H3 histone H3;p300:组蛋白乙酰基转移酶p300 histone acetyltransferase p300;Ac:乙酰化acetylation;acH3K9:乙酰化组蛋白H3第9赖氨酸acetylation histone H3 at lysine 9;acH3K27:乙酰化组蛋白H3第27赖氨酸acetylation histone H3 at lysine 27;acH3K56:乙酰化组蛋白H3第56赖氨酸acetylation histone H3 at lysine 56;P:磷phosphorus;degradation:降解;activation:激活;phosphorylation:磷酸化;Other pathway:其他途径。 图 1 HDAC抑制剂促进肠道抗菌肽表达的机制 Fig. 1 Mechanism of expression of antimicrobial peptides enhanced by HDAC inhibitors[3]
4 激活沉默信息调节因子(sirtuin,SIRT)与抑制HDAC存在交互作用

在哺乳动物中已发现18种HDAC,细分为5类,Ⅰ类:HDAC1、HDAC2、HDAC3、HDAC8;Ⅱa类:HDAC4、HDAC5、HDAC7、HDAC9;Ⅱb类:HDAC6、HDAC10;Ⅲ类SIRT1~7;Ⅳ类:HDAC11[19]。不同的去乙酰化酶调控相似的细胞进程,表明它们之间存在协调模式。HDAC抑制剂主要是抑制锌离子(Zn2+)依赖的去乙酰化酶,而SIRT1~7依赖于烟酰胺腺嘌呤二核苷酸(NAD+)[20-21]。因此,HDAC抑制剂对SIRT1~7没有抑制作用。近年来研究表明,SIRT1在维持肠道黏膜屏障完整性中发挥重要作用[22-23]。研究发现,SIRT1激活剂(白藜芦醇)提高小鼠细胞Cathelicidin抗菌肽(CRAMP)表达[24]。SIRT1是NAD+依赖去乙酰化酶,而烟酸是体内合成NAD+的主要来源[25]。Hwang等[26]研究表明,在体内烟酸或者烟酰胺提高细胞内NAD+水平而激活SIRT1。Bettenworth等[27]研究发现,烟酸提高抗菌肽CRAMPLF的表达,提高小鼠抵抗病原菌雷登枸橼酸杆菌(C. rodentium)感染能力。Hashimoto等[14]研究揭示,添加烟酰胺显著提高小鼠小肠上皮细胞抗菌肽的表达,缓解色氨酸缺乏或者血管紧张素转化酶2(ACE2)敲除引起的肠道炎症和腹泻。以上研究提示,SIRT1激活可能与烟酸提高肠道抗菌肽表达密切相关。烟酸在肠道上皮细胞和免疫细胞中与丁酸共用识别受体G蛋白偶联受体109A(GPR109A),作用与丁酸类似[28]。而丁酸是通过抑制HDAC3而提高肠道抗菌肽表达[5]。那么,SIRT1激活与HDAC抑制是否在调控肠道抗菌肽表达中存在交互作用呢?Scuto等[29]研究发现,激活SIRT1会抑制基因启动子区域与NF-κB/信号传导及转录激活因子3(STAT3)复合体结合,从而增强HDAC抑制剂介导的生长抑制DNA损伤基因45γ(GADD45γ)上调。Yaseen等[30]研究表明,SIRT1激活剂(白藜芦醇)与HDAC抑制剂在细胞NF-κB激活中存在对话机制。以上研究提示,SIRT1激活与HDAC抑制之间存在交互作用,但SIRT1与哪种HDAC相互作用及其对肠道抗菌肽表达的调控作用,还有待深入研究。

5 HDAC介导营养物质调控肠道抗菌肽表达的可能机制

抗菌肽是肠道上皮抵抗病原菌入侵的关键因子。HDAC和SIRT共同发挥作用调控肠道抗菌肽表达。HDAC抑制调节组蛋白修饰提升肠道抗菌肽表达,SIRT1激活促进肠道抗菌肽表达,且HDAC抑制与SIRT1激活之间存在交互作用。HDAC和SIRT1是营养物质调控肠道抗菌肽的主要靶点。基于上述研究结果与分析,我们推测HDAC介导营养物质精准调控肠道抗菌肽表达的可能机制为:营养物质通过抑制HDAC、激活SIRT1调节抗菌肽基因启动子区域组蛋白H3修饰方式(acH3K9、acH3K27、acH3K56、pH3S10等),从而促进肠道抗菌肽转录表达,增强肠道上皮抗病原菌感染能力(图 2)。

SIRT1:沉默信息调节因子1 sirtuin-1;HDAC:组蛋白去乙酰化酶histone deacetylases;NAD+:烟酰胺腺嘌呤二核苷酸nicotinamide adenine dinucleotide;AMPs:抗菌肽antimicrobial peptides;H3:组蛋白H3 histone H3;pH3S10:组蛋白H3丝氨酸10磷酸化phosphorylation of histone H3 at serine 10;ac:乙酰化acetylation;pr:磷酸化phosphorylation;acH3K9:乙酰化组蛋白H3第9赖氨酸acetylation histone H3 at lysine 9;acH3K27:乙酰化组蛋白H3第27赖氨酸acetylation histone H3 at lysine 27;acH3K56:乙酰化组蛋白H3第56赖氨酸acetylation histone H3 at lysine 56。 图 2 HDAC介导营养物质调控肠道抗菌肽表达的可能机制 Fig. 2 Possible mechanisms of HDAC mediating nutrient regulation of intestinal AMPs expression
6 小结

本文揭示了HDAC对肠道抗菌肽的调控作用及其介导营养物质促进抗菌肽表达的可能机制,在动物生产上具有理论和现实意义。目前,关于HDAC调控肠道抗菌肽表达的研究较少,有许多问题亟需研究:1)不同种类HDAC在调控肠道抗菌肽表达中的作用;2)SIRT1与何种HDAC交互作用并调控肠道抗菌肽表达;3)HDAC如何感应肠上皮细胞营养物质变化;4)HDAC如何调控组蛋白氨基酸残基的修饰方式。期待未来可更深入的研究HDAC调控肠道抗菌肽表达的机制,基于HDAC高效筛选促进畜禽肠道抗菌肽表达的营养素,有效提升肠道免疫力,改善肠道健康,提高动物生长性能。

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