细菌核酸诱导滋养细胞死亡及其机制研究
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摘要
单增李斯特菌是一类重要的人畜共患的胞内致病菌，可造成妊娠过程中严重的母胎感染。该病原是为数不多的可穿过胎盘屏障的病原菌，因而常作为研究母胎界面病原与母体互作的模式菌。
众所周知，机体诱导组织细胞的死亡，是先天免疫系统中对抗病原感染的重要机制。来自胞内病原菌或是病毒的双链DNA成分作为重要的病原相关分子模式，能够被模式识别受体识别，介导免疫应答反应，是先天免疫系统发挥抗感染作用的重要环节。对于滋养细胞如何感受并识别脂多糖，双链RNA等病原相关分子模式已有详尽的报道，而滋养细胞如何识别来自病原的双链DNA，它在妊娠的维持中有何意义仍不清楚。为了进一步了解滋养细胞能否感受外源的双链DNA并诱导相关的免疫反应，本研究利用人工合成的双链DNA，即poly (dA: dT)转染滋养细胞。通过MTT和流式分析发现，poly (dA: dT)可以剂量依赖的方式诱导滋养细胞的死亡。caspase和PARP在细胞死亡中会发生显著的活化，因而在细胞死亡鉴定中具有重要的意义。转染poly (dA: dT)到滋养细胞后，PARP发生了显著的活化。而泛caspase抑制剂可以抑制poly (dA: dT)诱导的部分的滋养细胞的死亡。因而，poly (dA: dT)诱导的滋养细胞的死亡除了有依赖于caspase的细胞死亡之外，应该存在一类不依赖于caspase的细胞死亡。
坏死性凋亡是最新发现的不依赖于caspase的一类程序性的细胞死亡。该类细胞死亡存在其特定的信号活化通路。RIPK1和RIPK3是该类细胞死亡的两种特异性的蛋白。RIPK1抑制剂Necrostatin-1（Nec-1）和/或RIPK3下游信号分子MLKL的抑制剂Necrosulfonamide （NSA）可以抑制多数诱导剂诱导的坏死性凋亡。本研究发现，在多种滋养细胞中，如HTR-8/SVneo、BeWo、JAR和JEG-3细胞中都有RIPK1、RIPK3、FADD和caspase8等细胞死亡相关蛋白的表达，其中RIPK3呈现弱表达。转染poly (dA: dT)后，RIPK1和RIPK3的基因和蛋白水平显著的上调。此外，免疫荧光染色发现poly (dA: dT)诱导的RIPK3蛋白的表达主要集中在细胞核内。
为了研究poly (dA: dT)诱导的细胞死亡中是否有坏死性凋亡的存在，我们应用了RIPK1和RIPK3-MLKL的特异性抑制剂做了以下的研究。在caspase受抑制或不受抑制的情况下分别加入Nec-1和/或NSA，并通过MTT、LDH、Western-Blot和流式细胞术检测poly (dA: dT)诱导的细胞死亡的变化情况。结果发现，无论caspase的活性是否受到抑制，Nec-1和NSA对poly (dA: dT)诱导的细胞死亡均无显著的影响。
为了进一步分析是否由于RIPK3在滋养细胞上的弱表达导致该细胞对dsDNA诱导的坏死性凋亡信号不敏感。本课题通过体外构建RIPK3的过表达质粒转染入滋养细胞，并筛选稳定高表达RIPK3的滋养细胞做进一步的研究。然而，在RIPK3呈现过表达的滋养细胞中，poly (dA: dT)诱导细胞死亡也非坏死性凋亡。同时，RIPK3过表达后，caspase和PARP的活化与对照组相比也无显著增加的趋势。此外，坏死性凋亡的经典活化分子，TNF-α在RIPK3过表达或非过表达状态下都不能诱导坏死性凋亡的发生。然而， TNF-α信号对poly (dA: dT)诱导的滋养细胞死亡有显著的促进作用。总之，以上的实验表明poly (dA: dT)可以诱导坏死性凋亡重要组件RIPK1和RIPK3的基因和蛋白的表达，然而RIPK1和RIPK3的表达与滋养细胞中坏死性凋亡的发生无关。而poly (dA: dT)在滋养细胞中诱导的细胞死亡主要为细胞凋亡。
众所周知，细胞发生坏死时，会迅速发生胞膜破裂，从而释放胞内的一系列的损伤相关分子模式。这些分子可以被模式识别受体识别，诱导机体组织细胞的过度炎症反应，对组织细胞造成损伤。然而，凋亡细胞发生裂解之前，通常会被周围的吞噬细胞所吞噬，并促进释放抑制炎症反应的IL-10和TGF-β等细胞因子。如上所述，即使在RIPK3蛋白过表达的情况下，滋养细胞仍对坏死性凋亡的各类刺激因子不敏感。滋养细胞受到病原微生物感染时，更倾向于发生凋亡而非坏死，这种选择性死亡可能是滋养细胞内在的妊娠保护机制
本课题进一步分析了病原来源的DNA成分是否与人工合成的DNA有相似的效应。我们提取单增李斯特菌的基因组DNA后，转染滋养细胞。结果发现，单增李斯特的基因组DNA以剂量依赖的方式诱导滋养细胞的死亡。同时，转染单增李斯特的基因组DNA后，滋养细胞中PARP的活化显著增加。细胞死亡中LDH的释放可以被caspase的抑制剂显著的抑制，而RIPK1和RIPK3的抑制剂无显著的效应。因而，以上的分析表明，病原来源的基因组DNA与人工合成的DNA在诱导滋养细胞死亡方面具有相似的效应。此外，敲除IFI16受体后，滋养细胞死亡显著降低，死亡率从17%降到10%。敲除AIM2对于poly (dA: dT)诱导细胞死亡无显著的影响。总之，以上的研究表明，病原核酸进入滋养细胞后，可以被IFI16受体识别，介导滋养细胞的凋亡，从而发挥有效的抗病原微生物感染的作用。
Pathogenic Nucleic Acid of Bacterium Induces Trophoblast Cell Death
Listeria monocytogenes, an intracellular pathogen, is an important cause ofmaternal-fetal infections. It can spread to the placenta and fetus, serves as a modelorganism to study placental barrier.
The death of infected cells is an important host innate defense mechanism. Doublestranded DNA (dsDNA) introduced by intracellular bacteria and dsDNA virus duringinfection, was identified as a potent PAMP. Immune sensing of cytosolic dsDNA hasemerged as a central component of antimicrobial innate defense. While the response oftrophoblast cells to PAMP such as LPS has been extensively studied, little is knownabout the direct effects of cytosolic dsDNA. To analyze the effect of cytosolic foreignDNA delivery on cell survival of trophoblasts cells, poly (dA: dT), a double-strandedhomopolymer with poly dA annealed to poly dT were used. Transfection with poly (dA:dT) on HTR-8/SVneo cell resulted a dose-dependent cell death using MTT and AnnexinV-PI assay. Caspase activation and PARP cleavage is the key event of cell death.Transfection with poly (dA: dT) on HTR-8/SVneo cell induced PARP cleavage.Caspase inhibitor z-VAD-fmk partially inhibited cell death after transfected with poly(dA: dT). Thus, there probably exists a caspase-independent cell death induced by poly(dA: dT) in trophoblast cells.
Necroptosis is a new cell death passway which are independent of caspase. Itexhibits a unique signaling pathway that requires the involvement of receptorinteraction protein kinase1and3(RIPK1and RIPK3) and can be specifically inhibitedby necrostatins and/or NSA. The first trimester trophoblast cell line HTR-8/SVneo,BeWo, JAR and JEG-3cells constitutively expressed RIPK1, RIPK3, FADD andcaspase8mRNA, as demonstrated by semi-quantitative RT-PCR. RIPK1and RIPK3were expressed in human first-trimester placenta tissue. Furthermore, the gene andprotein expression of RIPK1and RIPK3were all increased after transfected with poly(dA: dT). Meanwhile, immunofluorescence demonstrated the protein expression and thelocation of RIPK3after transfected with poly (dA: dT). Together these results indicatedthat poly (dA: dT) transfection promoted gene and protein expression of RIPK1andRIPK3, the protein of RIPK3were mostly located in nucleus.
In order to measure whether cell death induced by poly (dA: dT) was directly responsible for necroptosis, specific inhibitor of RIPK1and MLKL, a proteindownstream of RIPK3were used. Transfect poly (dA: dT) in the presence or absence ofthe pan-caspase inhibitor z-VAD-fmk, RIPK1inhibitor Nec-1or MLKL inhibitor NSAin trophoblast cells. Cell death was determined using MTT, LDH, Western-Blot andAnnexin V-PI assay. Caspase inhibitor z-VAD-fmk but not Nec-1and NSA may partiallyinhibit caspase activation, PARP cleavage and cell death induced by poly (dA: dT).Moreover, the liberation of LDH induced by poly (dA: dT) were also inhibit byz-VAD-fmk to some extent. Meanwhile, on the condition of inhibit caspase, Nec-1and/or NSA have no effect on cell death induced by poly (dA: dT).
For futher determin whether low expression of RIPK3in trophoblast cells give riseto insensitivity of dsDNA induced necroptosis signal. Stable over expression system forRIPK3were used after screening. Unfortunately, necroptosis was not found aftertransfected with poly (dA: dT) in over expression RIPK3trophoblast cells. Caspaseactivation and PARP cleavage were all not increased in over expression RIPK3trophoblast cells. Moreover, Cell death of necroptosis induced by TNF-α andz-VAD-fmk can not be found even if RIPK3is over expression in trophoblast cells.Taken together, these observations suggested that dsDNA may induce the mRNA andprotein of RIPK1and RIPK3expression, while the increased protein of RIPK3may notused for necroptosis.
It is often stated that necrosis often provoke inflammation. Morphologically,apoptotic cells initially maintain plasma membrane integrity and don't rapidly releasetheir intracellular contents. Before apoptotic cells disintegrate, they are usually ingestedby resident phagocytes. Moreover, phagocytosis of apoptotic cells stimulates theproduction of IL-10and TGF-β, which inhibit inflammation. Thus, it is reasonable thatthe invulnerability of trophoblasts to necroptosis induction contributes to placentalbarrier against PAMPs.
To investigate the effect of genomic DNA of pathogen on trophoblast cells duringinfection, several concentration of genomic DNA of Listeria monocytogenes were used.Cell death was found after transfection with genomic DNA of Listeria monocytogenesin a dose dependent manner. Furthermore, PARP cleavage was also detected introphoblast cells after transfected with genomic DNA of Listeria monocytogenes. LDHliberation was inhibited by z-VAD-fmk but not RIPK1and MLKL inhibitor.Theseobservations suggested that genomic DNA of Listeria monocytogenes may also induce cell death in trophoblat cells in parallel with poly (dA: dT). Knockdown of AIM2withsmall interfering RNA had no effect on poly (dA: dT)-induced cell death. However, celldeath induced by poly (dA: dT) was inhibited to some extent in the IFI16knockdowntrophoblasts, cell death rate were reduced from17%to10%. Taken together, cytosolicdsDNA induced IFI16-dependent, but AIM2-independent, apoptosis of humantrophoblast cells.
众所周知，机体诱导组织细胞的死亡，是先天免疫系统中对抗病原感染的重要机制。来自胞内病原菌或是病毒的双链DNA成分作为重要的病原相关分子模式，能够被模式识别受体识别，介导免疫应答反应，是先天免疫系统发挥抗感染作用的重要环节。对于滋养细胞如何感受并识别脂多糖，双链RNA等病原相关分子模式已有详尽的报道，而滋养细胞如何识别来自病原的双链DNA，它在妊娠的维持中有何意义仍不清楚。为了进一步了解滋养细胞能否感受外源的双链DNA并诱导相关的免疫反应，本研究利用人工合成的双链DNA，即poly (dA: dT)转染滋养细胞。通过MTT和流式分析发现，poly (dA: dT)可以剂量依赖的方式诱导滋养细胞的死亡。caspase和PARP在细胞死亡中会发生显著的活化，因而在细胞死亡鉴定中具有重要的意义。转染poly (dA: dT)到滋养细胞后，PARP发生了显著的活化。而泛caspase抑制剂可以抑制poly (dA: dT)诱导的部分的滋养细胞的死亡。因而，poly (dA: dT)诱导的滋养细胞的死亡除了有依赖于caspase的细胞死亡之外，应该存在一类不依赖于caspase的细胞死亡。
坏死性凋亡是最新发现的不依赖于caspase的一类程序性的细胞死亡。该类细胞死亡存在其特定的信号活化通路。RIPK1和RIPK3是该类细胞死亡的两种特异性的蛋白。RIPK1抑制剂Necrostatin-1（Nec-1）和/或RIPK3下游信号分子MLKL的抑制剂Necrosulfonamide （NSA）可以抑制多数诱导剂诱导的坏死性凋亡。本研究发现，在多种滋养细胞中，如HTR-8/SVneo、BeWo、JAR和JEG-3细胞中都有RIPK1、RIPK3、FADD和caspase8等细胞死亡相关蛋白的表达，其中RIPK3呈现弱表达。转染poly (dA: dT)后，RIPK1和RIPK3的基因和蛋白水平显著的上调。此外，免疫荧光染色发现poly (dA: dT)诱导的RIPK3蛋白的表达主要集中在细胞核内。
为了研究poly (dA: dT)诱导的细胞死亡中是否有坏死性凋亡的存在，我们应用了RIPK1和RIPK3-MLKL的特异性抑制剂做了以下的研究。在caspase受抑制或不受抑制的情况下分别加入Nec-1和/或NSA，并通过MTT、LDH、Western-Blot和流式细胞术检测poly (dA: dT)诱导的细胞死亡的变化情况。结果发现，无论caspase的活性是否受到抑制，Nec-1和NSA对poly (dA: dT)诱导的细胞死亡均无显著的影响。
为了进一步分析是否由于RIPK3在滋养细胞上的弱表达导致该细胞对dsDNA诱导的坏死性凋亡信号不敏感。本课题通过体外构建RIPK3的过表达质粒转染入滋养细胞，并筛选稳定高表达RIPK3的滋养细胞做进一步的研究。然而，在RIPK3呈现过表达的滋养细胞中，poly (dA: dT)诱导细胞死亡也非坏死性凋亡。同时，RIPK3过表达后，caspase和PARP的活化与对照组相比也无显著增加的趋势。此外，坏死性凋亡的经典活化分子，TNF-α在RIPK3过表达或非过表达状态下都不能诱导坏死性凋亡的发生。然而， TNF-α信号对poly (dA: dT)诱导的滋养细胞死亡有显著的促进作用。总之，以上的实验表明poly (dA: dT)可以诱导坏死性凋亡重要组件RIPK1和RIPK3的基因和蛋白的表达，然而RIPK1和RIPK3的表达与滋养细胞中坏死性凋亡的发生无关。而poly (dA: dT)在滋养细胞中诱导的细胞死亡主要为细胞凋亡。
众所周知，细胞发生坏死时，会迅速发生胞膜破裂，从而释放胞内的一系列的损伤相关分子模式。这些分子可以被模式识别受体识别，诱导机体组织细胞的过度炎症反应，对组织细胞造成损伤。然而，凋亡细胞发生裂解之前，通常会被周围的吞噬细胞所吞噬，并促进释放抑制炎症反应的IL-10和TGF-β等细胞因子。如上所述，即使在RIPK3蛋白过表达的情况下，滋养细胞仍对坏死性凋亡的各类刺激因子不敏感。滋养细胞受到病原微生物感染时，更倾向于发生凋亡而非坏死，这种选择性死亡可能是滋养细胞内在的妊娠保护机制
本课题进一步分析了病原来源的DNA成分是否与人工合成的DNA有相似的效应。我们提取单增李斯特菌的基因组DNA后，转染滋养细胞。结果发现，单增李斯特的基因组DNA以剂量依赖的方式诱导滋养细胞的死亡。同时，转染单增李斯特的基因组DNA后，滋养细胞中PARP的活化显著增加。细胞死亡中LDH的释放可以被caspase的抑制剂显著的抑制，而RIPK1和RIPK3的抑制剂无显著的效应。因而，以上的分析表明，病原来源的基因组DNA与人工合成的DNA在诱导滋养细胞死亡方面具有相似的效应。此外，敲除IFI16受体后，滋养细胞死亡显著降低，死亡率从17%降到10%。敲除AIM2对于poly (dA: dT)诱导细胞死亡无显著的影响。总之，以上的研究表明，病原核酸进入滋养细胞后，可以被IFI16受体识别，介导滋养细胞的凋亡，从而发挥有效的抗病原微生物感染的作用。
Pathogenic Nucleic Acid of Bacterium Induces Trophoblast Cell Death
Listeria monocytogenes, an intracellular pathogen, is an important cause ofmaternal-fetal infections. It can spread to the placenta and fetus, serves as a modelorganism to study placental barrier.
The death of infected cells is an important host innate defense mechanism. Doublestranded DNA (dsDNA) introduced by intracellular bacteria and dsDNA virus duringinfection, was identified as a potent PAMP. Immune sensing of cytosolic dsDNA hasemerged as a central component of antimicrobial innate defense. While the response oftrophoblast cells to PAMP such as LPS has been extensively studied, little is knownabout the direct effects of cytosolic dsDNA. To analyze the effect of cytosolic foreignDNA delivery on cell survival of trophoblasts cells, poly (dA: dT), a double-strandedhomopolymer with poly dA annealed to poly dT were used. Transfection with poly (dA:dT) on HTR-8/SVneo cell resulted a dose-dependent cell death using MTT and AnnexinV-PI assay. Caspase activation and PARP cleavage is the key event of cell death.Transfection with poly (dA: dT) on HTR-8/SVneo cell induced PARP cleavage.Caspase inhibitor z-VAD-fmk partially inhibited cell death after transfected with poly(dA: dT). Thus, there probably exists a caspase-independent cell death induced by poly(dA: dT) in trophoblast cells.
Necroptosis is a new cell death passway which are independent of caspase. Itexhibits a unique signaling pathway that requires the involvement of receptorinteraction protein kinase1and3(RIPK1and RIPK3) and can be specifically inhibitedby necrostatins and/or NSA. The first trimester trophoblast cell line HTR-8/SVneo,BeWo, JAR and JEG-3cells constitutively expressed RIPK1, RIPK3, FADD andcaspase8mRNA, as demonstrated by semi-quantitative RT-PCR. RIPK1and RIPK3were expressed in human first-trimester placenta tissue. Furthermore, the gene andprotein expression of RIPK1and RIPK3were all increased after transfected with poly(dA: dT). Meanwhile, immunofluorescence demonstrated the protein expression and thelocation of RIPK3after transfected with poly (dA: dT). Together these results indicatedthat poly (dA: dT) transfection promoted gene and protein expression of RIPK1andRIPK3, the protein of RIPK3were mostly located in nucleus.
In order to measure whether cell death induced by poly (dA: dT) was directly responsible for necroptosis, specific inhibitor of RIPK1and MLKL, a proteindownstream of RIPK3were used. Transfect poly (dA: dT) in the presence or absence ofthe pan-caspase inhibitor z-VAD-fmk, RIPK1inhibitor Nec-1or MLKL inhibitor NSAin trophoblast cells. Cell death was determined using MTT, LDH, Western-Blot andAnnexin V-PI assay. Caspase inhibitor z-VAD-fmk but not Nec-1and NSA may partiallyinhibit caspase activation, PARP cleavage and cell death induced by poly (dA: dT).Moreover, the liberation of LDH induced by poly (dA: dT) were also inhibit byz-VAD-fmk to some extent. Meanwhile, on the condition of inhibit caspase, Nec-1and/or NSA have no effect on cell death induced by poly (dA: dT).
For futher determin whether low expression of RIPK3in trophoblast cells give riseto insensitivity of dsDNA induced necroptosis signal. Stable over expression system forRIPK3were used after screening. Unfortunately, necroptosis was not found aftertransfected with poly (dA: dT) in over expression RIPK3trophoblast cells. Caspaseactivation and PARP cleavage were all not increased in over expression RIPK3trophoblast cells. Moreover, Cell death of necroptosis induced by TNF-α andz-VAD-fmk can not be found even if RIPK3is over expression in trophoblast cells.Taken together, these observations suggested that dsDNA may induce the mRNA andprotein of RIPK1and RIPK3expression, while the increased protein of RIPK3may notused for necroptosis.
It is often stated that necrosis often provoke inflammation. Morphologically,apoptotic cells initially maintain plasma membrane integrity and don't rapidly releasetheir intracellular contents. Before apoptotic cells disintegrate, they are usually ingestedby resident phagocytes. Moreover, phagocytosis of apoptotic cells stimulates theproduction of IL-10and TGF-β, which inhibit inflammation. Thus, it is reasonable thatthe invulnerability of trophoblasts to necroptosis induction contributes to placentalbarrier against PAMPs.
To investigate the effect of genomic DNA of pathogen on trophoblast cells duringinfection, several concentration of genomic DNA of Listeria monocytogenes were used.Cell death was found after transfection with genomic DNA of Listeria monocytogenesin a dose dependent manner. Furthermore, PARP cleavage was also detected introphoblast cells after transfected with genomic DNA of Listeria monocytogenes. LDHliberation was inhibited by z-VAD-fmk but not RIPK1and MLKL inhibitor.Theseobservations suggested that genomic DNA of Listeria monocytogenes may also induce cell death in trophoblat cells in parallel with poly (dA: dT). Knockdown of AIM2withsmall interfering RNA had no effect on poly (dA: dT)-induced cell death. However, celldeath induced by poly (dA: dT) was inhibited to some extent in the IFI16knockdowntrophoblasts, cell death rate were reduced from17%to10%. Taken together, cytosolicdsDNA induced IFI16-dependent, but AIM2-independent, apoptosis of humantrophoblast cells.
引文
[1]胡文艳.双链RNA对细胞凋亡和HBV复制的影响及细胞黏附对药物诱导凋亡的影响[D]:重庆医科大学,2011.
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