2. 动物抗病营养教育部重点实验室, 成都 611130
2. Key Laboratory of Animal Disease-Resistant Nutrition, Ministry of Education, Chengdu 611130, China
在动物生产中,许多炎性疾病如猪的肠炎、奶牛的乳房炎等,会削弱动物健康状况和生产力[1-2]。因此,缓解炎症反应对保证动物健康非常重要。研究发现,胆碱能神经系统在调控炎症反应中发挥重要作用[3]。在败血症猪上,刺激传出迷走神经降低了活化单核细胞数量,缓解了多器官功能障碍[4];仔猪腹泻则伴随着回肠黏膜迷走神经递质乙酰胆碱含量的降低[5]。α7烟碱型乙酰胆碱受体(α7-nicotinic acetylcholine receptor,α7nAChR)是烟碱型乙酰胆碱受体的一种亚型,是介导突触间快速信号传递的配体门控离子通道蛋白,在巨噬细胞、淋巴细胞等免疫细胞中均有表达[3]。研究发现,青年母猪发生子宫内膜炎时,子宫内膜和肌层α7nAChR蛋白表达降低[6];抑制α7nAChR表达后提高了脂多糖(lipopolysaccharide,LPS)诱导的牡蛎血细胞中肿瘤坏死因子(tumor necrosis factor,TNF)表达[7];与野生型小鼠相比,α7nAChR缺失提高了LPS诱导的小鼠血清中炎性细胞因子含量,同时电刺激迷走神经不能降低LPS诱导的α7nAChR缺失小鼠血清中炎性细胞因子含量[8]。以上结果说明,α7nAChR在胆碱能神经系统介导的抗炎途径中是必需的。本文拟就α7nAChR介导的抗炎作用与作用机制作一综述。
1 α7nAChR简述 1.1 α7nAChR蛋白结构α7nAChR属于神经递质门控离子通道超家族,是由5个独立α7亚基组装成的一个同型五聚体[3]。鸡、大鼠和人α7亚基均含有502个氨基酸残基,包括由23个氨基酸残基组成的信号肽[9-11],斑马鱼α7亚基则含509个氨基酸残基[12]。鸡α7成熟亚基有479个氨基酸,与大鼠、斑马鱼和人α7亚基同源性分别为79%、76%和88%[11-12];其N末端胞外区含有3个糖基化位点、5个半胱氨酸(Cys)残基,并含有4个α螺旋结构的跨膜区[11]。N末端胞外的3个糖基化位点和其中4个Cys残基及胞内区第365位丝氨酸(Ser365)磷酸化位点在鸡、大鼠、斑马鱼和人上是保守的。
1.2 α7nAChR蛋白分布α7nAChR在神经系统分布的主要区域为:大脑灰质、海马、基底神经节、丘脑、视叶及视网膜等,其表达分布的细胞主要包括脑区海马星形胶质细胞、成熟树突状细胞、小胶质细胞等[3];此外,α7nAChR在哺乳动物血管内皮细胞、支气管上皮细胞、胸腺上皮细胞、T淋巴细胞、B淋巴细胞、血液白细胞、单核细胞、巨噬细胞等均有表达[3, 13],且其结构和功能与神经节上的神经元α7nAChR相似。在斑马鱼上,α7nAChR在后脑及其附近区域有表达[12]。α7nAChR在神经、循环、呼吸、免疫系统中的广泛分布,表明其很可能与多种疾病之间存在联系。
2 α7nAChR介导的抗炎作用及其机制 2.1 α7nAChR介导的抗炎作用α7nAChR在调控动物炎症反应中具有重要作用。研究发现,α7nAChR敲除加剧了肾炎小鼠肾脏损伤和炎性细胞浸润[14]以及结肠炎小鼠的结肠炎症[15]。抑制α7nAChR活化则加重了大鼠胰腺炎[16]、LPS诱导的大鼠肝脏组织炎性细胞浸润[17]以及关节炎小鼠软骨变性[18]。激活α7nAChR则缓解了结肠炎小鼠的结肠组织损伤[19]、LPS诱导的大鼠回肠损伤[20]以及败血症导致的和LPS诱导的小鼠肺脏损伤[21-22],但是加剧了关节炎小鼠关节肿胀[23]。以上结果说明,α7nAChR参与了动物炎症反应的调控,且对不同组织器官炎症的调控存在差异。
细胞因子是炎症反应的主要介质,TNF-α、白细胞介素(interleukin,IL)-1等是重要的炎性细胞因子,能调控其他炎症介质的产生。研究发现,α7nAChR敲除提高了小鼠血清中IL-1β含量[24]以及结肠炎小鼠血清中IL-1β、IL-6和TNF-α含量[15]。抑制α7nAChR活化提高了肺脏损伤兔肺脏组织中TNF-α和IL-6含量[25]以及右美托嘧啶处理的急性肝脏损伤[17]和急性胰腺炎[16]大鼠血清中TNF-α和IL-6含量,但降低了LPS诱导的小鼠骨髓来源的单核/巨噬细胞中TNF-α和IL-10含量[26]。激活α7nAChR则降低了结肠炎小鼠结肠组织中IL-6和干扰素-γ(interferon-γ,IFN-γ)含量[19],烧伤小鼠血清中IL-6含量[27],肺脏损伤大鼠肺脏中TNF-α、IL-1β和IL-6含量[28],以及LPS诱导的小鼠血清[29]、星形胶质细胞[30]和单核巨噬细胞[31]中TNF-α和IL-6含量。以上结果表明,α7nAChR能介导调控炎性细胞因子的产生进而调节炎症反应。
细胞因子的产生受到基因和蛋白质水平的调控。α7nAChR介导的细胞因子含量变化可能与其参与调控细胞因子基因表达、蛋白质合成有关。研究发现,α7nAChR敲除提高了肾炎小鼠肾脏[14]和心肌梗塞小鼠脾脏[32]TNF-α、IL-1β和IL-6等细胞因子基因表达。抑制α7nAChR活化提高了右美托嘧啶处理的急性肝损伤大鼠肝脏组织TNF-α和IL-6的基因表达[17]。激活α7nAChR则降低了烧伤小鼠胫前肌中IL-1β和IL-6基因表达[27],以及LPS诱导的小鼠海马体、前额皮质区[33]和单核巨噬细胞J774[34]中TNF-α和IL-1β基因表达。这说明α7nAChR能介导调控细胞因子基因表达。此外,激活α7nAChR降低了LPS诱导的小鼠星形胶质细胞[30]和单核巨噬细胞J774[34]中TNF-α蛋白表达以及LPS诱导的大鼠神经元-小神经胶质细胞共培养中TNF-α和IL-1β蛋白表达[35],说明α7nAChR能介导调控细胞因子蛋白质合成。以上结果说明,α7nAChR介导的抗炎作用可能通过调控细胞因子的基因表达、蛋白质合成来实现。
2.2 α7nAChR介导的抗炎作用机制经典的α7nAChR活化产生的胞内效应由离子通道介导,在一些非神经细胞中,如T细胞中,α7nAChR活化能提高胞内钙离子(Ca2+)浓度[36]。在神经元和非神经元细胞中,α7nAChR活化还能通过活化双面神激酶2(Janus kinase 2,JAK2)和磷酸肌醇3激酶(phosphatidylinositol 3-kinase,PI3K)引起丝氨酸/苏氨酸激酶(Akt)磷酸化[37]。研究表明,α7nAChR介导的抗炎作用可能主要通过核转录因子-κB(nuclear factor-kappa B,NF-κB)信号途径与JAK2-信号传导与转录激活子3(signal transducer and activator of transcription 3,STAT3)信号途径实现。
2.2.1 NF-κB信号途径NF-κB信号途径在调控炎症反应中发挥重要作用,参与调节多种细胞因子的表达[3]。研究发现,激活α7nAChR降低了LPS诱导的心肌损伤小鼠心肌组织中NF-κB/p65的表达[38],烧伤小鼠肌肉[27]和子痫前期病人单核细胞中NF-κB活性[39],LPS诱导的小鼠单核巨噬细胞中NF-κB/p65磷酸化[31, 34],LPS诱导的小鼠星形胶质细胞中NF-κB核转位及其活性[30],以及小鼠炎性脂肪细胞中NF-κB/p60和p65的转录活性[40]。抑制α7nAChR活化则增加了LPS诱导的心肌损伤小鼠心肌组织[38]和慢性阻塞性肺病大鼠肺脏组织中NF-κB表达[41],心搏停止大鼠大脑皮质和海马体中NF-κB磷酸化水平[42],右美托嘧啶处理的急性肝损伤大鼠肝脏组织中NF-κB/p65磷酸化[17],以及LPS诱导的人支气管上皮细胞中NF-κB/p65的表达和转录活性[43]。这说明α7nAChR介导的抗炎作用与NF-κB密切相关。静息状态下,NF-κB通常以p50-p65异二聚体的形式与NF-κB抑制蛋白(inhibitor nuclear factor-kappa B,IκB)结合而呈非活化状态;当IκB被IκB激酶(IκB kinase,IKK)磷酸化进而泛素化被降解后,p65和/或者p50亚基进入细胞核调控相关基因表达。同时,NF-κB受到上游信号分子Toll样受体4(Toll-like receptor 4,TLR4)和髓样分化蛋白88(myeloid differential protein 88,MyD88)的调控。研究发现,激活α7nAChR抑制了LPS诱导的小鼠单核巨噬细胞和星形胶质细胞中IκB磷酸化[30-31],并抑制了LPS诱导的小鼠单核巨噬细胞中IKKα/β磷酸化[31]以及心肺分流术导致的大鼠海马区TLR4和MyD88基因和蛋白表达[44]。抑制α7nAChR活化提高了LPS诱导的人支气管上皮细胞[43]和右美托嘧啶处理的急性肝损伤大鼠肝脏组织[17]中IκB的磷酸化。以上结果说明,α7nAChR活化后能抑制IκB的降解,进而抑制NF-κB核转位,最终抑制炎性细胞因子表达,缓解炎症反应。
2.2.2 JAK2-STAT3信号途径JAK2-STAT3信号途径在调控细胞因子表达、炎症反应中发挥重要作用[45]。α7nAChR介导的抗炎作用可能与JAK2-STAT3信号途径密切相关。研究发现,激活α7nAChR活化提高了LPS活化的小鼠巨噬细胞中STAT3磷酸化,且不能降低STAT3活性缺失小鼠巨噬细胞中TNF-α表达[45];提高了小鼠炎性脂肪细胞中STAT3S727磷酸化[40];但降低了烧伤小鼠肌肉[27]和小鼠单核巨噬细胞[34]中STAT3磷酸化以及小鼠炎性脂肪细胞中STAT3Y705磷酸化[40]。抑制α7nAChR则阻止了尼古丁诱导的小鼠巨噬细胞和人冠状动脉内皮细胞中STAT3磷酸化[45-46]。STAT3能被胞质中JAK2激活。进一步研究表明,抑制α7nAChR提高了慢性阻塞性肺病大鼠肺脏组织中JAK2表达[41],而抑制JAK2磷酸化后抑制了α7nAChR活化诱导的小鼠巨噬细胞中STAT3磷酸化[45]。以上研究结果表明,α7nAChR活化能通过JAK2-STAT3信号途径发挥抗炎作用,但在不同组织器官炎症或损伤模式下的作用方式存在差异。
2.2.3 其他途径除了NF-κB和JAK/STAT3途径外,α7nAChR介导的抗炎作用还可能与其他信号通路有关,如胞外信号调节激酶(ERK)、p38丝裂原活化蛋白激酶(p38 MAPK)、环磷酸腺苷(cAMP)与蛋白激酶A(PKA)等。研究发现,激活α7nAChR活化抑制了LPS诱导的小鼠腹膜巨噬细胞中ERK、JNK与p38 MAPK磷酸化[21]。此外,前列腺素E2(prostaglandin E2,PGE2)能提高cAMP含量与PKA活性。研究表明,激活α7nAChR活化提高了LPS活化的人单核细胞中PEG2含量,而抑制α7nAChR则降低了PEG2含量,说明α7nAChR活化后可能通过调节内源PGE2的产生来发挥抗炎作用[47]。
3 营养物质通过α7nAChR对炎症反应的调控作用越来越多的研究发现,多种营养素,包括精氨酸(Arg)、ω-3脂肪酸、维生素D3、胆碱等能够提高动物免疫功能。研究表明,一些营养物质可以通过激活迷走神经缓解动物炎症,调节动物免疫功能。Niijima等[48]报道,静脉注射Arg与赖氨酸(Lys)提高了大鼠胸腺迷走传出神经活性和胸腺T细胞释放,而对肝脏迷走神经切除大鼠没有影响,说明Arg与Lys可以通过迷走神经调节大鼠免疫功能。另外,高脂饲粮能降低出血性休克大鼠血液中TNF-α与IL-6含量,而化学阻滞迷走传入神经或切断迷走神经抑制了这一作用[49-50],说明高脂饲粮能通过迷走神经调节动物炎症。
进一步研究发现,营养物质能通过α7nAChR调节动物炎症反应。高脂饲粮降低了LPS诱导的小鼠肺泡巨噬细胞和肺间质巨噬细胞[51]以及母鼠后代肝脏[52]中α7nAChR蛋白表达,但提高了大鼠下丘脑外侧和腹中侧α7nAChR与配体的结合[53];抑制和激活α7nAChR则分别抑制了高脂饲粮降低出血性休克大鼠血液中TNF-α与IL-6含量的作用[50]和高脂诱导的小鼠肝细胞中TNF-α与IL-6基因表达[52]。胆碱是一个内源性α7nAChR激动剂[54]。研究发现,饲粮胆碱缓解了脑损伤导致的大鼠大脑海马体等区域α7nAChR活性下降及脑部炎症[55],但降低了LPS诱导的大鼠胎盘α7nAChR蛋白表达[56];注射胆碱则上调了LPS处理的小鼠海马区α7nAChR表达及活性[57],且不能降低α7nAChR敲除小鼠血清中TNF-α含量[58],说明胆碱能通过活化α7nAChR调控动物炎症反应。此外,Arg提高了大鼠前额皮质和海马体α7nAChR蛋白表达[59];维生素D3降低了糖尿病大鼠大脑皮层[60]和小脑[61]α7nAChR基因表达;而蛋氨酸-胆碱缺乏诱导了α7nAChR敲除小鼠肝脏中TNF基因表达[62]。以上结果说明,饲粮脂肪水平、胆碱、维生素D3等营养因素可能通过α7nAChR调控动物炎症。
肠内信号可以通过活化位于迷走传入神经纤维的化学感受器激活迷走神经[63]。胆囊收缩素1受体(CCK-1R)则是位于迷走传入神经纤维上的化学感受器之一[64]。在大鼠上的研究表明,抑制CCK-1R表达能抑制高脂饲粮降低出血性休克大鼠血液中TNF-α与IL-6含量的作用,而抑制α7nAChR表达也有同样的作用,说明高脂饲粮可能通过活化迷走传入神经上的CCK-1R,刺激迷走神经,活化α7nAChR调节动物炎症[49-50]。这一结果说明,肠内营养可能通过激活迷走传入神经,进而活化α7nAChR调控动物炎症反应。
4 小结与展望α7nAChR广泛存在于神经细胞与多种免疫细胞中,其活化后可以通过阻止IκB降解和p65核转位、调控NF-κB转录活性进而调控细胞因子的产生,缓解炎症;同时还可以通过JAK2-STAT3信号途径调控细胞因子表达,产生抗炎作用。近年来,α7nAChR介导的抗炎作用越来越受到研究者的关注,并被广泛用于治疗人类多种炎性疾病。但对于α7nAChR介导的抗炎作用在动物上研究较少,且其活化后胞内信号传递机制,尤其是不同信号通路之间的相互作用研究较少,有待进一步研究。此外,α7nAChR在营养物质调控炎症反应中的作用研究非常少,有必要开展相关研究,为动物抗病营养研究提供新的支撑。
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