小鼠巨噬细胞胞外陷阱的性质研究与旋毛虫活性脱氧核糖核酸酶的鉴定
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摘要
先天性免疫细胞胞外陷阱（ETs）是近年来新发现的一种先天性免疫防御机制。当嗜中性粒细胞受到外源微生物或某些化学物质刺激后，会向细胞外释放出主要由DNA和颗粒蛋白组成的纤维状结构，该结构能够捕获并杀灭多种细胞外微生物，在嗜酸性粒细胞和肥大细胞中也发现了这种机制的存在。其中嗜中性粒细胞和肥大细胞通过细胞核DNA与颗粒蛋白融合后以挤压的方式释放到细胞外，而嗜酸性粒细胞则通过弹射的方式释放主要由线粒体DNA构成的胞外陷阱。来源于细胞核的ETs释放方式通常会导致细胞的死亡，这种死亡方式具有既不同于凋亡也不同于坏死的特征，被认为是一种新的细胞死亡程序-NETosis；而线粒体弹射的ETs释放通常来自于活细胞，可在数秒内完成整个过程。目前发现能够诱导ETs的微生物包括细菌、真菌和原虫，但寄生线虫是否能够诱导该机制尚未见报道。虽然目前关于巨噬细胞存在ETs的现象已经得到报道（在本研究进行的过程中），但对于其是否与其他先天性免疫细胞的ETs具有相似的性质目前依旧未知。
旋毛虫是一种典型的人兽共患寄生线虫，可经消化道感染并长期寄生于宿主的肌细胞中。其感染特点之一就是能够逃避宿主的先天性免疫防御机制，如在感染病灶处虽然可见先天性免疫细胞的聚集，却并不发生明显的炎性的反应。排泄/分泌（ES）抗原被认为在旋毛虫免疫逃避机制中发挥主要作用，其成分复杂，含有多种酶类，可直接作用于机体免疫细胞参与调控。本实验室前期工作通过免疫筛选获得旋毛虫的28条期特异性DNaseⅡ抗原基因，免疫荧光分子定位显示其在新生幼虫中定位于整个表皮，在成虫中定位于表皮cord细胞以及在肌幼虫中定位于杆状体，而三者皆为旋毛虫不同发育时期的分泌器官，因此推测旋毛虫DNaseⅡ可能参与其免疫逃避过程。由于ETs主要成分为DNA，我们推断旋毛虫DNaseⅡ的功能之一可能是降解先天性免疫细胞对其进行捕获的ETs。
在本论文中，我们以小鼠来源的巨噬细胞为实验对象，对微生物诱导的巨噬细胞ETs进行了研究。首先，我们通过激光共聚焦显微镜和扫描电子显微镜发现大肠杆菌和白色念珠菌都能够诱导巨噬细胞向细胞外释放纤维状结构，该结构主要成分为DNA且能够粘附细菌及真菌，因此我们确定其为巨噬细胞胞外陷阱（METs）。同时，我们研究了其他非病原菌刺激物诱导METs的效果，结果显示β-溶血素和酵母多糖都能够诱导METs的产生，但PMA、LPS和过氧化氢等其他细胞常用的ETs诱导剂对巨噬细胞并无诱导效果，显示巨噬细胞可能有自己独特的METs激发机制。同时对METs的定量实验显示其产量与微生物感染数量呈剂量依赖性，且微生物在较短时间（小于15min）内即可刺激METs的生成。
其次，我们对METs形成的相关性质进行了研究。免疫荧光实验显示METs上存在多种抗菌蛋白，包括组蛋白、酸性磷酸酶、溶菌酶和髓过氧化物酶；但组蛋白和酸性磷酸酶仅在部分METs上出现，提示巨噬细胞中可能存在不止一种类型的METs。通过PCR和荧光原位杂交技术，我们发现细胞核来源的DNA和线粒体来源的DNA都能够定位于METs；而死亡细胞崩解产生的METs和活细胞喷射的METs也都同时在巨噬细胞中被发现；以上结果显示巨噬细胞同时存在核崩解和线粒体弹射两种ETs形成机制。此外我们还测定了METs对大肠杆菌和白色念珠菌的杀菌效率，结果显示METs介导的杀菌作用并不显著；为了确证该结果的可靠性，我们对METs捕获的大肠杆菌和白色念珠菌进行了原位活/死染色，荧光显微镜观察结果显示活细胞释放的METs完全不具有杀菌能力，而细胞死亡崩解产生的METs虽能杀死少量细菌但效果有限。我们同时还检测了METs的产生是否依赖ROS及细胞凋亡，结果显示巨噬细胞释放ETs并不依赖ROS及凋亡。因此，巨噬细胞ETs既有与嗜中性粒细胞等相似的性质，也有自己独特的特点。
再次，我们研究了巨噬细胞针对旋毛虫感染是否也存在METs机制。利用激光共聚焦显微镜和扫描电子显微镜，我们发现存活的旋毛虫并不能明显诱导METs的产生，但当核酸酶抑制剂ATA存在时，巨噬细胞就能释放METs捕获并部分杀死旋毛虫新生幼虫及肌幼虫。我们同时发现利用抗旋毛虫血清并不能封闭这种逃避METs捕获的机制，在抗体存在时，旋毛虫依旧不能被METs捕获，但却可以被巨噬细胞所吞噬。而METs机制对旋毛虫的杀灭作用要显著高于吞噬作用。
最后，我们对旋毛虫ES产物中的核酸酶活性成分进行了研究。通过DNA底物切割实验及切割产物末端基团测定，我们发现肌幼虫和成虫/新生幼虫ES产物中确实存在核酸酶活性且为DNaseⅡ型。我们首先利用大肠杆菌对已知的不同发育时期的DNaseⅡ（P43和T3223）进行原核表达和活性鉴定，结果显示肌幼虫时期（P43）和成虫期（T3223）特异性DNaseⅡ并不具有核酸酶活性。由于原核表达无法对蛋白进行糖基化等修饰，我们同时利用离子交换层析、凝胶过滤层析和免疫亲和层析技术对ES产物中天然P43及T3223蛋白进行了纯化，结果确定P43蛋白没有活性而T3223蛋白具有活性。通过SDS-PAGE酶谱实验分析，我们发现ES产物中的核酸酶活性来源于多种分子量大小的蛋白组分，且丰度极低；加之旋毛虫ES难于大量收集，直接对活性成分进行纯化困难重重。因此我们建立了一种针对核酸酶二维电泳酶谱分析方法，利用活性凝胶二维电泳结合串联质谱分析，成功地对旋毛虫ES产物中核酸酶活性成分进行了分离鉴定，为进一步研究旋毛虫逃避先天性免疫细胞ETs捕获的分子机制奠定了基础。
Neutrophil extracellular traps (NETs) is an important innate immune defencemechanism which was discovered only a few years ago. After being stimulated bysome pathogenic microbes or chemical regents, neutrophil release extracellularfibrous structure which iscomposed of DNA and granular proteins. This structurecould ensnare and kill varied kinds of invading microbes. This new mechanism wasalso reported to exist in eosinophil and mast cells. Two models describing the releaseof extracellular traps (ETs) have been proposed: extrusion of mixed nuclear DNA withgranular proteins in neutrophil and mast cells, and catapult-like releasing ofmitochondrial DNA in eosinophil. Nuclear originated ETs releasing often need2-3hours and lead to cell death, while mitochondrial originated ETs was released byintact cells and occurred in several seconds. Cell death induced by ETs formationshows characters different from apoptosis or necrosis, which was designated to be anew cell death pathway named NETosis. Reported ETs-inducing microbes includebacteria, fungi and protozoa, but whether pathogenic parasitic nematodes also induceETs is still unknown. Besides neutrophil, eosinophil and mast cells, the ETsmechanism exists in macrophages is still less known and need to be furtherinvestigated.
Trichinella spiralis is a typical pathogenic nematode. Ingestion of uncooked orhalf-cooked T. spiralis contaminated meat lead to human or animal trichinellosis. Thelarvae could parasitize in host’s muscle for a long time. A characteristic of T. spiralisinfection is inefficiency of host innate immune system. For example, T. spiralisinvading to intestine cells leads to innate immune cells assembling, but lacks offollowing inflammatory reaction. The excretion/secretion (ES) product of T. spiralis is believed to play a key role in immune escape process of T. spiralis. The ES productcontains varied kinds of proteins and enzymes, which could directly act on host’simmune cells to regulate immune response. Our previously work has identified28devolopmental stage-specific DNaseⅡgenes from Ts cDNA library by immunologicalscreening. Immunofluorescence experiments indicated that these DNaseⅡ locateincuticle of T. spiralis new born larvae, cord cells of adult worm and stichosome ofmuscle larvae, respectively. All of the three positions are main secretory organs of T.spiralis in different developmental stages. Because that the main function of DNaseⅡis to degrade DNA, we deduced Ts DNaseⅡ may help in degradation of ETs formedby innate immune cells.
In this study, we used murine macrophages cell line to investigate whether ETsmechanism also exist in macrophages. Firstly, E. coli and C. albicans infectedmacrophages were observed to release extracellular fiber-like structure by laserconfocal microscopy (LCM) and scanning electron microscope (SEM). Thesestructures contain DNA component and are able to ensnare bacteria and fungi, whichexhibited the same features with NETs. So they were named “MacrophageExtracellular Traps (METs)”. Non-pathogen stimulus displayed different abilities toinduce METs formation. Hemolysin and zymosan were efficient regents to stimulatemacrophage releasing METs, while PMA, LPS and hydrogen peroxide, which arepowerful stimulus of NETs, displayed limited METs inducing activity. Thisphenomenon indicates macrophage may have different ETs formation mechanismcompared with other innate immune cells. We also found that the quantity of METsformation was depended on the concentration of stimulus, and that the formation ofMETs occurred in a short time (less than15min) after incubation with pathogens.
Secondly, we investigated the characteristic of METs. Immunofluorescence ofMETs shown some anti-microbe enzymes co-localized with extracellular DNA,including histone, tartrate-resistant acid phosphatase (TRAP), lysozyme andmyeloperoxidase (MPO). Interestingly, not all METs contain histone and TRAP,indicating there may be more than one type of METs existing in murine macrophages.By PCR and fluorescence in situ hybridization (FISH) experiments, we observed bothnuclear and mitochondrial DNA existing in METs. We also observed both cell death-associated METs and living cell released METs coexisting in macrophage. Thisphenomenon indicates that macrophage could release METs in either nuclear DNApathway or mitochondrial pathway. We also evaluated the antimicrobial activity ofMETs by modified plate assay. Result showed METs had limited capability to kill E.coli and C. albicans. In order to corroborate this finding, we conducted in situLive/Dead fluorescence stain of METs ensnared microbes. Fluorescence microscopeobservation revealed living cell released METs didn’t kill microbes at all, while celldeath associated METs could kill only very few E. coli and limite several C. albicansto germinated. Moreover, we investigated the relationship between METs and ROS,and whether METs lead to cell death in apoptosis pathway. We found neither ROSproduction nor apoptosis behavior occurred in METs formation process.
Thirdly, we investigated whether METs can response to pathogenic nematode T.spiralis. LCM and SEM observation revealed living T.spiralis muscle larvae ornewborn larvae did not induce METs. But macrophage can produce METs to ensnareand kill T. spiralis in present of nuclease inhabitor aurintricarboxylic acid (ATA).Interestingly, the less the T.spiralis was added to macrophages cultures, the longgertime needed to induce METs production. So we deduced that METs may also inducedby ES component. Our following experiment confirmed this deduction. We also foundanti-T. spiralis serum cannot block this escape mechanism. T. spiralis was notensnared by METs in present of anti-T. spiralis antibodies, but in this case, weobserved phagocytosis of newborn larvae by macrophage. METs were more effectiveto kill newborn larvae than phagocytosis.
Lastly, we investigated the active nuclease component in T. spiralis ES products.By DNA substrate cleavage and intermediate product terminal group analyse, wefound nuclease activity existed in ES products and display DNaseⅡ characteristic.We expressed the known DNaseⅡfrom differentmental develop stages (P43andT3223) in E. coli and analyse their activity. Unfortunately, recombinant muscle larvae(P43) and adult worm (T3223) specific DNaseⅡ showed no activity. In order tocorroborate this result, we purified native P43and T3223protein from correspondingES product by using ion exchange chromatography, gel filtration chromatography andimmunoaffinity chromatography. Activity analysis of these two native proteins suggested P43was inactive, while T3223possess activity. In order to identify theactive DNaseⅡ component, we performed SDS-PAGE zymography analysis of ESproducts. Result showed the DNaseⅡ activity in ES origined from several proteinswith different molecular weights. Because it’s difficult to collect enough ES fordirectly purifying active components, we established an2D nuclease zymographycombined NanoLC-ESI-MS/MS method to identify them. Our work provided a newway to identify nuclease from a small quantity samples, and the identified activenuclease was the candidates for further investigation of T. spiralis ETs-escapemechanism.
旋毛虫是一种典型的人兽共患寄生线虫，可经消化道感染并长期寄生于宿主的肌细胞中。其感染特点之一就是能够逃避宿主的先天性免疫防御机制，如在感染病灶处虽然可见先天性免疫细胞的聚集，却并不发生明显的炎性的反应。排泄/分泌（ES）抗原被认为在旋毛虫免疫逃避机制中发挥主要作用，其成分复杂，含有多种酶类，可直接作用于机体免疫细胞参与调控。本实验室前期工作通过免疫筛选获得旋毛虫的28条期特异性DNaseⅡ抗原基因，免疫荧光分子定位显示其在新生幼虫中定位于整个表皮，在成虫中定位于表皮cord细胞以及在肌幼虫中定位于杆状体，而三者皆为旋毛虫不同发育时期的分泌器官，因此推测旋毛虫DNaseⅡ可能参与其免疫逃避过程。由于ETs主要成分为DNA，我们推断旋毛虫DNaseⅡ的功能之一可能是降解先天性免疫细胞对其进行捕获的ETs。
在本论文中，我们以小鼠来源的巨噬细胞为实验对象，对微生物诱导的巨噬细胞ETs进行了研究。首先，我们通过激光共聚焦显微镜和扫描电子显微镜发现大肠杆菌和白色念珠菌都能够诱导巨噬细胞向细胞外释放纤维状结构，该结构主要成分为DNA且能够粘附细菌及真菌，因此我们确定其为巨噬细胞胞外陷阱（METs）。同时，我们研究了其他非病原菌刺激物诱导METs的效果，结果显示β-溶血素和酵母多糖都能够诱导METs的产生，但PMA、LPS和过氧化氢等其他细胞常用的ETs诱导剂对巨噬细胞并无诱导效果，显示巨噬细胞可能有自己独特的METs激发机制。同时对METs的定量实验显示其产量与微生物感染数量呈剂量依赖性，且微生物在较短时间（小于15min）内即可刺激METs的生成。
其次，我们对METs形成的相关性质进行了研究。免疫荧光实验显示METs上存在多种抗菌蛋白，包括组蛋白、酸性磷酸酶、溶菌酶和髓过氧化物酶；但组蛋白和酸性磷酸酶仅在部分METs上出现，提示巨噬细胞中可能存在不止一种类型的METs。通过PCR和荧光原位杂交技术，我们发现细胞核来源的DNA和线粒体来源的DNA都能够定位于METs；而死亡细胞崩解产生的METs和活细胞喷射的METs也都同时在巨噬细胞中被发现；以上结果显示巨噬细胞同时存在核崩解和线粒体弹射两种ETs形成机制。此外我们还测定了METs对大肠杆菌和白色念珠菌的杀菌效率，结果显示METs介导的杀菌作用并不显著；为了确证该结果的可靠性，我们对METs捕获的大肠杆菌和白色念珠菌进行了原位活/死染色，荧光显微镜观察结果显示活细胞释放的METs完全不具有杀菌能力，而细胞死亡崩解产生的METs虽能杀死少量细菌但效果有限。我们同时还检测了METs的产生是否依赖ROS及细胞凋亡，结果显示巨噬细胞释放ETs并不依赖ROS及凋亡。因此，巨噬细胞ETs既有与嗜中性粒细胞等相似的性质，也有自己独特的特点。
再次，我们研究了巨噬细胞针对旋毛虫感染是否也存在METs机制。利用激光共聚焦显微镜和扫描电子显微镜，我们发现存活的旋毛虫并不能明显诱导METs的产生，但当核酸酶抑制剂ATA存在时，巨噬细胞就能释放METs捕获并部分杀死旋毛虫新生幼虫及肌幼虫。我们同时发现利用抗旋毛虫血清并不能封闭这种逃避METs捕获的机制，在抗体存在时，旋毛虫依旧不能被METs捕获，但却可以被巨噬细胞所吞噬。而METs机制对旋毛虫的杀灭作用要显著高于吞噬作用。
最后，我们对旋毛虫ES产物中的核酸酶活性成分进行了研究。通过DNA底物切割实验及切割产物末端基团测定，我们发现肌幼虫和成虫/新生幼虫ES产物中确实存在核酸酶活性且为DNaseⅡ型。我们首先利用大肠杆菌对已知的不同发育时期的DNaseⅡ（P43和T3223）进行原核表达和活性鉴定，结果显示肌幼虫时期（P43）和成虫期（T3223）特异性DNaseⅡ并不具有核酸酶活性。由于原核表达无法对蛋白进行糖基化等修饰，我们同时利用离子交换层析、凝胶过滤层析和免疫亲和层析技术对ES产物中天然P43及T3223蛋白进行了纯化，结果确定P43蛋白没有活性而T3223蛋白具有活性。通过SDS-PAGE酶谱实验分析，我们发现ES产物中的核酸酶活性来源于多种分子量大小的蛋白组分，且丰度极低；加之旋毛虫ES难于大量收集，直接对活性成分进行纯化困难重重。因此我们建立了一种针对核酸酶二维电泳酶谱分析方法，利用活性凝胶二维电泳结合串联质谱分析，成功地对旋毛虫ES产物中核酸酶活性成分进行了分离鉴定，为进一步研究旋毛虫逃避先天性免疫细胞ETs捕获的分子机制奠定了基础。
Neutrophil extracellular traps (NETs) is an important innate immune defencemechanism which was discovered only a few years ago. After being stimulated bysome pathogenic microbes or chemical regents, neutrophil release extracellularfibrous structure which iscomposed of DNA and granular proteins. This structurecould ensnare and kill varied kinds of invading microbes. This new mechanism wasalso reported to exist in eosinophil and mast cells. Two models describing the releaseof extracellular traps (ETs) have been proposed: extrusion of mixed nuclear DNA withgranular proteins in neutrophil and mast cells, and catapult-like releasing ofmitochondrial DNA in eosinophil. Nuclear originated ETs releasing often need2-3hours and lead to cell death, while mitochondrial originated ETs was released byintact cells and occurred in several seconds. Cell death induced by ETs formationshows characters different from apoptosis or necrosis, which was designated to be anew cell death pathway named NETosis. Reported ETs-inducing microbes includebacteria, fungi and protozoa, but whether pathogenic parasitic nematodes also induceETs is still unknown. Besides neutrophil, eosinophil and mast cells, the ETsmechanism exists in macrophages is still less known and need to be furtherinvestigated.
Trichinella spiralis is a typical pathogenic nematode. Ingestion of uncooked orhalf-cooked T. spiralis contaminated meat lead to human or animal trichinellosis. Thelarvae could parasitize in host’s muscle for a long time. A characteristic of T. spiralisinfection is inefficiency of host innate immune system. For example, T. spiralisinvading to intestine cells leads to innate immune cells assembling, but lacks offollowing inflammatory reaction. The excretion/secretion (ES) product of T. spiralis is believed to play a key role in immune escape process of T. spiralis. The ES productcontains varied kinds of proteins and enzymes, which could directly act on host’simmune cells to regulate immune response. Our previously work has identified28devolopmental stage-specific DNaseⅡgenes from Ts cDNA library by immunologicalscreening. Immunofluorescence experiments indicated that these DNaseⅡ locateincuticle of T. spiralis new born larvae, cord cells of adult worm and stichosome ofmuscle larvae, respectively. All of the three positions are main secretory organs of T.spiralis in different developmental stages. Because that the main function of DNaseⅡis to degrade DNA, we deduced Ts DNaseⅡ may help in degradation of ETs formedby innate immune cells.
In this study, we used murine macrophages cell line to investigate whether ETsmechanism also exist in macrophages. Firstly, E. coli and C. albicans infectedmacrophages were observed to release extracellular fiber-like structure by laserconfocal microscopy (LCM) and scanning electron microscope (SEM). Thesestructures contain DNA component and are able to ensnare bacteria and fungi, whichexhibited the same features with NETs. So they were named “MacrophageExtracellular Traps (METs)”. Non-pathogen stimulus displayed different abilities toinduce METs formation. Hemolysin and zymosan were efficient regents to stimulatemacrophage releasing METs, while PMA, LPS and hydrogen peroxide, which arepowerful stimulus of NETs, displayed limited METs inducing activity. Thisphenomenon indicates macrophage may have different ETs formation mechanismcompared with other innate immune cells. We also found that the quantity of METsformation was depended on the concentration of stimulus, and that the formation ofMETs occurred in a short time (less than15min) after incubation with pathogens.
Secondly, we investigated the characteristic of METs. Immunofluorescence ofMETs shown some anti-microbe enzymes co-localized with extracellular DNA,including histone, tartrate-resistant acid phosphatase (TRAP), lysozyme andmyeloperoxidase (MPO). Interestingly, not all METs contain histone and TRAP,indicating there may be more than one type of METs existing in murine macrophages.By PCR and fluorescence in situ hybridization (FISH) experiments, we observed bothnuclear and mitochondrial DNA existing in METs. We also observed both cell death-associated METs and living cell released METs coexisting in macrophage. Thisphenomenon indicates that macrophage could release METs in either nuclear DNApathway or mitochondrial pathway. We also evaluated the antimicrobial activity ofMETs by modified plate assay. Result showed METs had limited capability to kill E.coli and C. albicans. In order to corroborate this finding, we conducted in situLive/Dead fluorescence stain of METs ensnared microbes. Fluorescence microscopeobservation revealed living cell released METs didn’t kill microbes at all, while celldeath associated METs could kill only very few E. coli and limite several C. albicansto germinated. Moreover, we investigated the relationship between METs and ROS,and whether METs lead to cell death in apoptosis pathway. We found neither ROSproduction nor apoptosis behavior occurred in METs formation process.
Thirdly, we investigated whether METs can response to pathogenic nematode T.spiralis. LCM and SEM observation revealed living T.spiralis muscle larvae ornewborn larvae did not induce METs. But macrophage can produce METs to ensnareand kill T. spiralis in present of nuclease inhabitor aurintricarboxylic acid (ATA).Interestingly, the less the T.spiralis was added to macrophages cultures, the longgertime needed to induce METs production. So we deduced that METs may also inducedby ES component. Our following experiment confirmed this deduction. We also foundanti-T. spiralis serum cannot block this escape mechanism. T. spiralis was notensnared by METs in present of anti-T. spiralis antibodies, but in this case, weobserved phagocytosis of newborn larvae by macrophage. METs were more effectiveto kill newborn larvae than phagocytosis.
Lastly, we investigated the active nuclease component in T. spiralis ES products.By DNA substrate cleavage and intermediate product terminal group analyse, wefound nuclease activity existed in ES products and display DNaseⅡ characteristic.We expressed the known DNaseⅡfrom differentmental develop stages (P43andT3223) in E. coli and analyse their activity. Unfortunately, recombinant muscle larvae(P43) and adult worm (T3223) specific DNaseⅡ showed no activity. In order tocorroborate this result, we purified native P43and T3223protein from correspondingES product by using ion exchange chromatography, gel filtration chromatography andimmunoaffinity chromatography. Activity analysis of these two native proteins suggested P43was inactive, while T3223possess activity. In order to identify theactive DNaseⅡ component, we performed SDS-PAGE zymography analysis of ESproducts. Result showed the DNaseⅡ activity in ES origined from several proteinswith different molecular weights. Because it’s difficult to collect enough ES fordirectly purifying active components, we established an2D nuclease zymographycombined NanoLC-ESI-MS/MS method to identify them. Our work provided a newway to identify nuclease from a small quantity samples, and the identified activenuclease was the candidates for further investigation of T. spiralis ETs-escapemechanism.
引文
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