2023, Vol. 18
中性粒细胞是血液循环系统中最丰富的白细胞，也是参与天然免疫应答的主要细胞之一，对维持机体稳态至关重要。宿主遭遇病原体感染时，中性粒细胞启动系列防御机制：①通过趋化游走作用聚集到感染部位；②通过形成胞内吞噬体脱颗粒杀伤病原体；③通过释放中性粒细胞胞外诱捕网(neutrophil extracellular trap，NET)捕获和阻止病原体扩散，维持局部高浓度的抗菌肽等物质用以降解和清除毒力因子[1]。中性粒细胞可利用NADPH氧化酶复合体(NADPH oxidase complex，NOX)衍生的活性氧(reactive oxygen species，ROS)、细胞毒性颗粒成分、抗菌肽和NET等物质，对病原体进行高效杀伤和降解以保护宿主。除中性粒细胞外，其他免疫细胞亦可产生胞外诱捕网，如嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞等[2]。NET是迄今研究最多的胞外诱捕网，参与机体的免疫应答。NET缺乏会导致某些疾病的发生，例如先天性或周期性中性粒细胞减少症患者常因NET产生不足而患牙周炎[3]。NET在参与抗感染的过程中也会引起免疫病理损伤，导致疾病发生，如系统性红斑狼疮、类风湿关节炎、心血管疾病、急性脑卒中和心肌梗死等[4]。
不同病原体调节NET释放的机制不尽相同。病毒诱导NET释放时依赖血小板的黏附性，在低病毒载量时NET能抑制病毒复制，在高病毒载量时NET作用有限，这与中性粒细胞的ACE181和TMPRSS19受体有关[5-6]。真菌可激活NOX依赖型和非依赖型NETosis，也可诱导自杀型和非自杀型NETosis，此过程中中性粒细胞表面的补体C3b受体具有重要作用。真菌还可通过生物膜、抑制NET形成和分泌酶来逃避NET的捕获和杀伤[7-9]。寄生虫如溶组织内阿米巴也能被NET捕获，但不影响其生长，只有小部分滋养体被杀死。细胞外囊泡在寄生虫诱导的NET形成中具有重要作用，如日本血吸虫可促进肝脏中细胞外囊泡释放而产生NET[5]。本文综述了NET与细菌相互作用机制的研究进展。
1 NET的发现及产生过程1996年，Takei等[10]首次观察到一种特别的中性粒细胞死亡方式：用12-豆蔻酸-13-乙酸佛波醇(phorbol 12-myristate 13-acetate，PMA)处理中性粒细胞后，随着核染色质从破碎的核膜和细胞膜中释放，细胞的形态发生了变化。2004年，Brinkmann等[11]在志贺菌实验中意外发现细菌被困在中性粒细胞外的一种丝状结构上，其组成包括中性粒细胞弹性蛋白酶(neutrophil elastase，NE)、DNA、组蛋白和一些散在颗粒等，他们将这种可捕获和杀伤细菌的胞外支架结构命名为NET。进一步研究发现，NET的释放始于对细菌的识别，激活NET相关途径并破坏细胞核膜和颗粒膜可将解聚的核DNA释放到胞质中，而解聚的DNA、瓜氨酸化组蛋白及颗粒蛋白等在细胞质中首先形成NET，并以质膜的破坏和网状结构的胞外释放而告终[12]。中性粒细胞释放NET的过程被称为NETosis，这是除细胞凋亡、坏死之外的又一种细胞死亡方式[13]。
中性粒细胞释放NET时有非常明显的形态学变化。活化后的扁平细胞牢固地附着在底物上，之后分叶核小叶消失，染色质解聚，核膜内外层分离，细胞质部分颗粒降解，随后核膜分解成单独的囊泡且核质和细胞质融合成均匀团块，最后细胞恢复圆形并收缩至细胞膜破裂释放细胞内容物——NET[14]。研究证实，NET的生成方式有自杀型和非自杀型NETosis，后者分为无需ROS参与的依赖细胞核DNA释放型和需要ROS参与的依赖线粒体DNA(mitochondrial DNA，mtDNA)释放型[15]。
自杀型NETosis依赖NOX产生的大量ROS、蛋白激酶C(protein kinase C，PKC)和Raf-MEK-ERK信号通路，以及肽酰基精氨酸脱亚氨酶4(protein arginine deiminase type 4，PAD4)介导的组蛋白瓜氨酸化引起的染色质解聚。髓过氧化物酶(myeloperoxidase，MPO)和NE从颗粒中释放并转移到胞核，有助于染色质进一步解聚；核膜破裂使释放的染色质与胞质蛋白混合，释放NET后致中性粒细胞死亡。这种NET的形成被认为是中性粒细胞的自杀，是机体应对感染的天然免疫应答，区别于细胞凋亡和坏死[15]。非自杀型NETosis又称“真实NETosis”，不依赖Raf-MEK-ERK信号通路。中性粒细胞受刺激后，通常通过Toll样受体(Toll-like receptor，TLR)或补体受体与C3蛋白配体结合使核膜形态改变，以不破坏细胞膜完整性的囊泡出芽方式释放NET，之后细胞膜重新融合，保持原有的活性，继续行使趋化和吞噬等功能[16]。
2 NET的形成机制 2.1 NET的主要组成及功能NET主要含有染色质、组蛋白、颗粒蛋白、消皮素D(gasdermin D，GSDMD)、钙卫蛋白、成孔蛋白、白细胞蛋白酶3(proteinase 3，PR3)、抗菌肽、组织蛋白酶G(cathepsin G，CG)和细胞质蛋白等成分[11-13]。NET中的DNA主要由核DNA或mtDNA组成。染色质与捕获和杀伤入侵细菌的颗粒以及核蛋白缠绕在一起形成NET的框架，具有隔离表面结合的阳离子、破坏膜完整性和裂解细菌的功能，其快速的杀菌活性还启动了细菌逃避宿主抗感染免疫应答的信号[17]。在某些特定条件下，NET可只由mtDNA组成，通过环鸟苷酸腺苷酸合成酶-干扰素基因刺激因子(cyclic GMP-AMP synthase-stimulator of interferon gene，cGAS-STING)信号通路和TLR9途径激活中性粒细胞，并促进NET中的NE和DNA产生。同时，mtDNA还增加了ROS的产生及NET相关蛋白Rac 2和PAD4的表达，进一步促进NET形成[18]。NET形成后由DNase降解并被巨噬细胞吞噬。DNase 1和DNase 3对于NET清除至关重要，缺乏这2种酶的小鼠在中性粒细胞激活后，因为NET不能及时清除而导致血管闭塞，小鼠在几天内死亡[19]。
组蛋白是NET的主要蛋白成分，其中核心组蛋白为H2A、H2B、H3和H4，占NET相关蛋白的70%。组蛋白能将DNA包装成染色质，既是有效的抗菌物质，又有细胞毒性，从而对机体造成损伤[20]。在不杀死细胞的情况下，组蛋白和DNA的协同作用在调节信号转导中具有重要意义——组蛋白激活TLR4的同时DNA将TLR4募集至组蛋白的核内体中诱导NET产生[21]。
颗粒蛋白在中性粒细胞转运、反向经内皮迁移、发挥吞噬和胞葬作用、维持细胞寿命和细胞因子活性、形成NET以及自身免疫应答等方面发挥重要调节作用[22]。NE和MPO存在于中性粒细胞的嗜天青颗粒中。NE是中性粒细胞特异性丝氨酸蛋白酶，可使组蛋白裂解而促进染色质解聚，还可通过细胞周期蛋白依赖性激酶4/6(cyclin-dependent kinases 4/6，CDK4/6)和PKC介导核膜破裂，使其自身在NET形成早期进入细胞核，发挥降解毒力因子和杀灭细菌的作用[23]。MPO以被动扩散的方式通过核孔进入细胞核，蛋白质组学分析表明，不同刺激诱导的NET在蛋白质合成和翻译后修饰方面不尽相同，其中MPO是更为广泛修饰的蛋白质[20, 24-25]。
GSDMD是一种形成孔隙的蛋白，其在NET形成过程中被NE水解激活并与其形成前反馈回路——激活的GSDMD在颗粒膜上打孔促进NE释放，该过程进一步促进GSDMD的激活并在细胞膜上打孔，从而促进NET的释放[13]。钙卫蛋白能与一些重金属离子(如锌离子和锰离子)形成螯合物，调控炎症反应和机体免疫应答。在炎症过程中，受刺激的中性粒细胞会释放钙卫蛋白，随后与MPO产生的次氯酸结合，该可逆过程增强了钙卫蛋白对中性粒细胞蛋白酶的敏感性，水解后被灭活[26]。
2.2 NET的释放机制脂多糖(lipopolysaccharide，LPS)、白细胞介素6(interleukin 6，IL-6)、IL-8、肿瘤坏死因子α(tumor necrosis factor α，TNF-α)、病原体和化学物质等均可诱导NOX依赖型NETosis[27]，其分子机制包括以下几个方面。①通过Raf-MEK-ERK途径激活NOX，刺激ROS产生[15]。②与特异性受体结合，导致胞内Ca2+浓度升高，使线粒体产生ROS并积累到一定程度激活NOX[28]。③LPS通过c-Jun氨基端激酶(c-Jun N-terminal kinase，JNK)/应激活化蛋白激酶(stress-activated protein kinase，SAPK)信号通路激活NOX依赖自杀型NETosis[29]。④ROS诱导的NETosis依赖NOX、磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinases，PI3K)、MPO和NE对组蛋白H2A和H2B的选择性降解[30]。⑤IL-33是新发现的广泛表达于多种组织的IL-1家族成员，刺激因子通过IL-33/ST2信号通路激活NOX产生ROS，诱导NET形成，从而激发宿主的天然免疫应答[31]。⑥NOX产生大量ROS，引起广泛的DNA损伤，随后DNA修复蛋白增殖细胞核抗原(proliferating cell nuclear antigen，PCNA)从细胞质进入细胞核进行修复，该修复过程也可诱导NETosis[32]。
被激活的NOX产生ROS，促进中性粒细胞颗粒释放NE和MPO，随后迁移到细胞核，促进染色体解聚和核膜破裂，这是NET形成的显著特征[33]。最后，细胞膜破裂，释放NET。CDK是NET的基本调节因子，可使G0期中性粒细胞快速返回细胞周期，抑制CDK4和CDK6表达可抑制NET释放，但不影响ROS产生及中性粒细胞脱颗粒和吞噬功能[34]。此NET产生的过程中NOX激活促使ROS产生是关键步骤，因此称为NOX依赖型NETosis(见图 1)。
此后，另一种不依赖NOX的NET形成方式被发现。其分子机制包括以下几个方面。①细胞质中Ca2+浓度增加，激活PAD4促进组蛋白瓜氨酸化使染色体解聚，该过程需要线粒体活性氧(mitochondrial ROS，mROS)的参与。②革兰氏阴性胞内菌的LPS通过caspase-11依赖性途径切割GSDMD，GSDMD直接在核膜和细胞膜上打孔诱导NET的合成和释放。此时只需要瓜氨酸化的组蛋白参与，不需要ROS和PAD4。③一些刺激通过NLRP3炎症小体途径激活caspase-1，进一步切割GSDMD[27]。④小GTP酶Cdc42缺乏时，通过激活SK通道诱导不依赖NOX的NETosis，并需要PKC和线粒体参与[35](见图 1)。NOX依赖型NETosis需要NE切割相关组蛋白的N端，而这在非依赖型NETosis中不会发生，这常作为2种NETosis的鉴别点[36]。
3 细菌与NET的相互作用革兰氏阳性菌的细胞壁含有肽聚糖、脂质、磷糖醛酸和磷壁酸，不同于由肽聚糖和外膜(含脂质、蛋白质和LPS)组成的革兰氏阴性菌细胞壁。革兰氏阳性菌分泌酶和毒素致NET形成，革兰氏阴性菌外膜的主要成分LPS是诱导NET形成的有效刺激物。研究发现，LPS与中性粒细胞通过复杂的相互作用诱导自杀型和非自杀型NETosis，诱导结果取决于LPS来源及血小板是否存在[37]。
3.1 革兰氏阳性菌葡萄球菌中金黄色葡萄球菌毒力最强，其通过在宿主体内繁殖、扩散和产生有害胞外物质(酶和毒素)而导致疾病。金黄色葡萄球菌通过与吞噬受体和血小板相互作用及分泌毒力因子(如杀白细胞素、脂蛋白、脂肪酶、蛋白A和苯酚可溶性调节蛋白等)来诱导NET形成[38]。在金黄色葡萄球菌诱导的心内膜炎大鼠模型中发现，NET不仅捕获细菌，还能促进血小板聚集和受损心脏瓣膜脓毒性血栓形成[39]。金黄色葡萄球菌也进化出多种防御机制：①通过DNase降解DNA骨架使细菌从NET中逃脱；②分泌蛋白质Eap结合和聚集DNA来抑制NET形成；③通过表达表面蛋白——纤连蛋白结合蛋白B(fibronectin binding protein B，FnBPB)来中和组蛋白的杀菌活性以抵抗NET介导的杀伤作用；④形成生物膜以抑制NET的抗菌活性[40]。
肺炎链球菌常寄居于正常人的鼻咽腔，是细菌性大叶性肺炎、脑膜炎和支气管炎的主要病原菌。肺炎链球菌的α-烯醇化酶与中性粒细胞表面蛋白相互作用诱导NET形成[41]。肺炎链球菌所致社区获得性肺炎的不良预后与NET有关[42]。肺炎链球菌感染可导致肺损伤，此时中性粒细胞通过抑制ROS产生和NE向细胞核易位来减少NET释放[43]。在肺炎链球菌致急性中耳炎的过程中，TLR4调节ROS和中性粒细胞自噬以调控NET释放[44]。肺炎链球菌性脑膜炎患者脑脊液和中枢神经系统中的NET会阻碍细菌的清除，使用DNase I降解NET具有显著的治疗效果[45]。与细胞外囊泡有关的DNA酶TatD能有效降解NET，从而帮助肺炎链球菌逃脱[46]。肺炎链球菌的毒力因子表面蛋白A不仅能抵抗NET介导的杀伤作用，还能阻断细菌与NET的结合使其逃脱[47]。
结核分枝杆菌是兼性胞内菌，是导致人类结核病最重要和最常见的病原体，可侵犯全身各器官系统，以肺部最为常见。结核病是目前全球尤其是发展中国家危害最为严重的慢性传染病之一。结核分枝杆菌中的早期分泌抗原靶6(early secretory antigenic target 6，ESAT-6)可通过增加Ca2+内流和激活钙蛋白酶促进NET合成，该过程依赖ROS[48]。NET虽无法杀灭结核分枝杆菌，但NET骨架NDA中的热休克蛋白72是杀灭结核分枝杆菌所必需的，且中性粒细胞能促进具有更高杀伤能力的细胞募集和激活[49]。结核病患者体内中性粒细胞分泌的NE增多，金属基质蛋白酶9活性增强，但病变缺氧抑制了NET形成[50]。中枢神经系统结核是最严重的结核病形式，此类患者体内募集的中性粒细胞浸润大脑，执行脱颗粒、吞噬和NETosis的抗菌功能，从而引起中枢神经系统炎症、组织破坏和病理变化[51]。结核分枝杆菌细胞外因子Rv0888具有核酸酶和鞘磷脂酶活性，前者促使NET降解，后者可诱导NET形成，从而增强了结核分枝杆菌在肺部的定植[52]。
产单核细胞李斯特菌为兼性胞内杆菌，是一种食源性和机会致病菌，可引起李斯特病，主要表现为脑膜炎和败血症等。研究发现，宿主多配体蛋白聚糖-1可通过抑制血管内NET形成导致李斯特病[53]。小鼠感染李斯特菌后可刺激中性粒细胞迅速募集到相应部位(尤其是肝脏和脾脏)，并诱导NET捕获和杀伤细菌。促进黏附和脱颗粒的衔接蛋白在中性粒细胞发挥功能的过程中有重要作用，但其缺乏时几乎不影响NET捕获产单核细胞李斯特菌的功能[54]。
3.2 革兰氏阴性菌大肠埃希菌是肠道中重要的正常菌群，在宿主免疫力下降或细菌入侵肠道外组织器官后成为机会致病菌，其某些血清型具有致病性，是引发人类腹泻和泌尿系统感染等疾病的常见病原体。大肠埃希菌的LPS和菌毛能诱导NET形成[37]。大肠埃希菌也能抑制NET形成：尿路致病性大肠埃希菌的多功能毒力因子TcpC是MyD88靶向的E3泛素连接酶，可通过泛素蛋白酶体系统降解MyD88，阻断TLR信号通路，并促进PAD4泛素化降解以抑制NET形成[55]。某些药物可利用NET对大肠埃希菌的抑制作用来治疗相关疾病，如美金刚——具有电压依赖性和中等程度亲和力的非竞争性N-甲基-D-天[门]冬氨酸(N-methyl-D-aspartate, NMDA)受体拮抗剂，可有效治疗多重耐药大肠埃希菌引起的菌血症和脑膜炎[56]。近期研究发现，大肠埃希菌的脂蛋白能抑制中性粒细胞中NOX的活化而导致其杀菌活性降低，从而保护大肠埃希菌免于被中性粒细胞清除[57]。
肺炎克雷伯菌是医院获得性感染中最常见的病原菌之一，可刺激中性粒细胞介导的需要PAD4参与的NET形成[58]。非致病性肺炎克雷伯菌不影响中性粒细胞内ROS和MPO的产生，但可使吞噬溶酶体酸化而影响MPO功能[59]。高毒力肺炎克雷伯菌和经典肺炎克雷伯菌均能诱导NET形成，但前者对中性粒细胞吞噬和杀伤的抗性明显高于后者，且中性粒细胞仅对后者具有杀伤作用[60]。产碳青霉烯酶肺炎克雷伯菌的LPS能诱导少量NET合成，也可抑制ROS产生从而阻止NET释放[61]。适配器蛋白在肺炎克雷伯菌诱导NET形成过程中至关重要，如中性粒细胞中的适配器蛋白SKAP2依赖性信号转导促进ROS产生和清除细菌[62]。信号转导淋巴细胞活化分子相关蛋白是另一种含SH2结构域的适配器蛋白，主要存在于T细胞、自然杀伤(natural killer，NK)细胞和自然杀伤T细胞(natural killer T cell，NKT)。在肺炎克雷伯菌所致的急性肺炎中，若信号转导淋巴细胞活化分子相关蛋白缺乏，则NET合成减少，这是该蛋白的新功能，并可能成为肺脓毒症和NET相关疾病的药物靶点[63]。
沙门菌是兼性胞内菌，可引起胃肠炎、伤寒和败血症等，重者死亡。沙门菌Ⅲ型分泌系统和鞭毛可影响NET释放，且中性粒细胞释放的ROS可促进沙门菌在肠道中的生存和入侵[64]。在鼠伤寒沙门菌诱导NET形成过程中，NOX具有重要作用。RGK家族的小GTP酶是NOX的负调节剂，NOX缺乏时机体可通过增加NOX组装和NET产生而增强天然免疫应答[65]。NOX能使细胞内鼠伤寒沙门菌的ΔpH紊乱，但可通过糖酵解代谢重编程抵消：①鼠伤寒沙门菌将氧化还原平衡转变为糖酵解以减少通过膜的电子流，并满足能量要求生成三羧酸中间体；②将电子从呼吸链中移开；③糖酵解使细菌的胞膜蛋白在氧化应激期间折叠[66]。肠道感染鼠伤寒沙门菌后会继发感染肺炎克雷伯菌，中性粒细胞诱导释放的NET减少，而淋巴细胞、单核细胞、嗜酸性粒细胞和嗜碱性粒细胞没有明显变化[67]。部分细菌与NET的相互作用机制如表 1所示。
NET是一把“双刃剑”，一方面可捕获和消灭病原体，另一方面其过度释放或不能及时清除会导致血管闭塞、组织损伤及炎症加剧和迁移。深入研究NET与病原体的相互作用机制有望发现干预靶点，通过研发激活剂或阻滞剂调控NET的作用及功能，如抑制MPO释放、干扰MPO信号转导，以及用小分子抑制剂、重组蛋白抑制剂和促分解脂质介质(如脂氧素和溶解素)抑制MPO功能来调节NET，这有望成为治疗疾病的新方法。由于病原生物的多样性、细胞的异质性及研究方法的多样性，了解NET如何被诱导和释放一直具有挑战性，仍有许多问题亟待解决。
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