IL-7抑制巨噬细胞凋亡的机制研究
摘要
血吸虫病(schistosomiasis)是由血吸虫(schistosome)感染引起的一种人兽共患寄生虫病。血吸虫成虫产下的虫卵沉积于宿主肝脏中，引起严重的肝脏虫卵肉芽肿，从而继发肝纤维化，并最终导致门脉高压症等严重的继发症而使患者丧失劳动能力、生活自理能力甚至造成死亡。巨噬细胞作为肝脏虫卵肉芽肿中最主要的抗原递呈细胞，在虫卵肉芽肿的发生、发展中发挥了关键作用：首先，巨噬细胞吞噬虫卵抗原并将其加工后递呈给CD4+T细胞，从而激活T细胞应答，产生大量的细胞因子与趋化因子，是虫卵肉芽肿发生的始动因素；其次，巨噬细胞接触血吸虫卵抗原后，自身也可分泌趋化因子和细胞因子，与T细胞一起共同趋化包括巨噬细胞、噬酸性粒细胞、中性粒细胞、成纤维细胞等在内的多种细胞包绕虫卵形成虫卵肉芽肿。此外，巨噬细胞本身又是直接组成虫卵肉芽肿的最主要成分之一，占肉芽肿内所有细胞的30%。因此，鉴于巨噬细胞在血吸虫感染后宿主肝脏虫卵肉芽肿发生发展中的关键作用，我们有理由推测，巨噬细胞的凋亡可能会显著影响虫卵肉芽肿的发生、发展，从而显著影响血吸虫感染后对宿主的致病及其后果。
文献及本研究均证明血吸虫感染会诱导巨噬细胞发生凋亡，然而，我们发现，虽然血吸虫感染后宿主的凋亡巨噬细胞绝对数量在显著增加，但同时巨噬细胞的总数却显著增加、且凋亡细胞占总细胞数的比例却出现显著减少，是什么因素使得巨噬细胞凋亡比例减少？我们经研究发现，血吸虫感染后，可通过诱导主产生细胞因子IL-7来抑制巨噬细胞凋亡，使巨噬细胞绝对数量增加，从而加重肉芽肿反应、并最终可能加重宿主的肝脏免疫病理损害。
随后我们对IL-7抑制巨噬细胞凋亡的机制进行了探索，发现IL-7可以通过巨噬细胞表面的IL-7R（由IL-7Rα，又称CD127和IL-7Rγ，又称CD132组成）传递信号，抑制巨噬细胞自身凋亡以及由血吸虫可溶性虫卵抗原（SEA）诱导的巨噬细胞凋亡，并且IL-7抑制巨噬细胞凋亡可导致巨噬细胞数量增多，这一作用与IL-7处理后巨噬细胞的增殖变化无关。但是本研究发现，与以往报道的IL-7通过调控BCL-2蛋白质家族来发挥抑制T细胞凋亡作用这一机制不同的是，IL-7抑制巨噬细胞凋亡机制并不依赖BCL-2蛋白质家族。BCL-2蛋白质家族中的促凋亡蛋白可促进细胞色素C（cytochrome C）和Smac/Diablo从线粒体中释放从而促进Caspase的激活和凋亡的发生发展，BCL-2蛋白质家族中的抗凋亡蛋白作用则相反。同时，BCL-2蛋白质家族还可通过Caspase非依赖的途径来促进/抑制细胞凋亡。本研究发现IL-7对巨噬细胞的抑制凋亡作用主要通过Caspase非依赖途径（但尚不能排除有Caspase依赖途径的参与），还发现血吸虫感染及其虫卵抗原导致的小鼠巨噬细胞凋亡也不依赖BCL-2蛋白质家族和Caspase信号通路。最后，本研究发现作为一种Caspase非依赖机制之一，血吸虫抗原可能通过引起巨噬细胞自噬、最终导致凋亡，而IL-7正是抑制了巨噬细胞自身的自噬以及由血吸虫抗原引起的巨噬细胞自噬，从而抑制了巨噬细胞的凋亡。
总之，本研究首次发现了IL-7对T细胞以外的免疫细胞（巨噬细胞）也具有抗凋亡作用。同时，还创新性地发现IL-7具有与以往报道不同的Caspase非依赖性抑制巨噬细胞凋亡机制——抑制细胞自噬，这些成果不仅大大丰富和拓展了人们对IL-7抑制凋亡作用领域和机制的现有认识，而且对血吸虫性肝脏虫卵肉芽肿的临床控制具有潜在的指导意义。
Schistosomiasis is a parasitic disease caused by several species of trematodes(platyhelminth infection, or "flukes"), a parasitic worm of the genus Schistosoma.Eggs laid by the female worms trapped in the liver will cause severe hepaticgranulomas, progress of which will allow the development of fibrosis and finally leadto portal hypertension, and the patients will suffer from disablement and the loss ofself-care ability, they may even die at last. As the major antigen-presenting cells ingranulomas, macrophages play essential role in the occurrence and developmen of thegranulomas, first of all, macrophages engulf schistosome egg antigens and processthe antigens before presenting them to CD4+T cells, and thus activate T cell immuneresponse to produce abundance cytokines and chemokines which will initiategranuloma response; secondly, after exposure to the egg antigens, macrophagesthemselves will secrete cytokines and chemokines and together with T cells to recruitmultiple cells include macrophages, eosnophils, neutrophils and fibrocytes to formgranulomas by wrapping the eggs, whats more, as a component of the granulomas,macrophages are about30%of all the cells in granulomas. Macrophages are suchimportant cells for the development of hepatic granulomas, so it is logical for us tospeculate that the apoptosis of macrophages will markedly impact the development ofthe hepatic granulomas and thereby influence the pathopoiesis of schistosomeinfection.
Our research proved that schistosome infection would induce apoptosis in macrophages, however, we noticed that although the absolute numbers of apoptoticmacrophages apparently increased after schistosome infection, the total numbers ofmacrophages obviously increased and the percentages of apoptotic macrophagesdistinctly decreased, so what contributed to the decreased percentages of apoptoticmacrophages? We found that, cytokine IL-7was dramatically induced to increase thetotal numbers of macrophages by preventing the apoptosis of them. The increasedmacrophages thereby lead to the enhancement of hepatic granulomas, which maycontribute to the Immune pathological damage in liver.
Immediately after that we further explored the mechanisms of the prevention ofmacrophages apoptosis by IL-7. Results turned out that IL-7could signal through theIL-7R(consists of α chain, CD127, and γ chain, CD132) expressed on macrophages toprevent the apoptosis of macrophages and the apoptosis induced by soluble eggantigen(SEA). The function of increasing numbers of macrophages by IL-7was notinfluenced by the changes of macrophages proliferation after IL-7treatment.Different from previous studies which declared that IL-7prevents T cell apoptosis byup-regulating anti-apoptotic members and down-regulating pro-apoptotic members ofBCL-2protein family, our study found that IL-7prevented macrophages apoptosisindependent of BCL-2protein family. The pro-apoptotic members of BCL-2proteinfamily(BAX,BAK) works through promoting the release of cytochrome C andSmac/Diablo from mitochondria to activate caspases and promote apoptosis, whilethe anti-apoptotic members(BCL-2,BCL-XL) works on the contrary. However, BCL-2protein family can still promote or prevent cell apoptosis independent of caspases.This research found that IL-7could prevent macrophages apoptosis independent ofcaspases(but we could not rule out the impact of caspase-dependent pathway yet),and schistosome infection and the egg antigen induced macrophages apoptosis wereindependent of BCL-2protein family and caspases which could be prevented by IL-7 through the same way. Finally, our research indicated that SEA may inducedmacrophages apoptosis by induction of macrophages autophagy, while IL-7justinhibited macrophages autophagy to prevent macrophages apoptosis.
In a word, this research observed for the first time that IL-7could also preventapoptosis of immunocytes (macrophages) other than T cells. And we innovativelyfound that mechanisms underlying in the preventing apoptotic role of IL-7onmacrophages were independent of caspases while through inhibiting autophagy,which was different from previous studies. These results dramatically expanded theexisting reorganization of the preventing apoptotic function of IL-7, and can apply asclinical supervision for the control of hepatic granulomas in schistosomiasis.
文献及本研究均证明血吸虫感染会诱导巨噬细胞发生凋亡，然而，我们发现，虽然血吸虫感染后宿主的凋亡巨噬细胞绝对数量在显著增加，但同时巨噬细胞的总数却显著增加、且凋亡细胞占总细胞数的比例却出现显著减少，是什么因素使得巨噬细胞凋亡比例减少？我们经研究发现，血吸虫感染后，可通过诱导主产生细胞因子IL-7来抑制巨噬细胞凋亡，使巨噬细胞绝对数量增加，从而加重肉芽肿反应、并最终可能加重宿主的肝脏免疫病理损害。
随后我们对IL-7抑制巨噬细胞凋亡的机制进行了探索，发现IL-7可以通过巨噬细胞表面的IL-7R（由IL-7Rα，又称CD127和IL-7Rγ，又称CD132组成）传递信号，抑制巨噬细胞自身凋亡以及由血吸虫可溶性虫卵抗原（SEA）诱导的巨噬细胞凋亡，并且IL-7抑制巨噬细胞凋亡可导致巨噬细胞数量增多，这一作用与IL-7处理后巨噬细胞的增殖变化无关。但是本研究发现，与以往报道的IL-7通过调控BCL-2蛋白质家族来发挥抑制T细胞凋亡作用这一机制不同的是，IL-7抑制巨噬细胞凋亡机制并不依赖BCL-2蛋白质家族。BCL-2蛋白质家族中的促凋亡蛋白可促进细胞色素C（cytochrome C）和Smac/Diablo从线粒体中释放从而促进Caspase的激活和凋亡的发生发展，BCL-2蛋白质家族中的抗凋亡蛋白作用则相反。同时，BCL-2蛋白质家族还可通过Caspase非依赖的途径来促进/抑制细胞凋亡。本研究发现IL-7对巨噬细胞的抑制凋亡作用主要通过Caspase非依赖途径（但尚不能排除有Caspase依赖途径的参与），还发现血吸虫感染及其虫卵抗原导致的小鼠巨噬细胞凋亡也不依赖BCL-2蛋白质家族和Caspase信号通路。最后，本研究发现作为一种Caspase非依赖机制之一，血吸虫抗原可能通过引起巨噬细胞自噬、最终导致凋亡，而IL-7正是抑制了巨噬细胞自身的自噬以及由血吸虫抗原引起的巨噬细胞自噬，从而抑制了巨噬细胞的凋亡。
总之，本研究首次发现了IL-7对T细胞以外的免疫细胞（巨噬细胞）也具有抗凋亡作用。同时，还创新性地发现IL-7具有与以往报道不同的Caspase非依赖性抑制巨噬细胞凋亡机制——抑制细胞自噬，这些成果不仅大大丰富和拓展了人们对IL-7抑制凋亡作用领域和机制的现有认识，而且对血吸虫性肝脏虫卵肉芽肿的临床控制具有潜在的指导意义。
Schistosomiasis is a parasitic disease caused by several species of trematodes(platyhelminth infection, or "flukes"), a parasitic worm of the genus Schistosoma.Eggs laid by the female worms trapped in the liver will cause severe hepaticgranulomas, progress of which will allow the development of fibrosis and finally leadto portal hypertension, and the patients will suffer from disablement and the loss ofself-care ability, they may even die at last. As the major antigen-presenting cells ingranulomas, macrophages play essential role in the occurrence and developmen of thegranulomas, first of all, macrophages engulf schistosome egg antigens and processthe antigens before presenting them to CD4+T cells, and thus activate T cell immuneresponse to produce abundance cytokines and chemokines which will initiategranuloma response; secondly, after exposure to the egg antigens, macrophagesthemselves will secrete cytokines and chemokines and together with T cells to recruitmultiple cells include macrophages, eosnophils, neutrophils and fibrocytes to formgranulomas by wrapping the eggs, whats more, as a component of the granulomas,macrophages are about30%of all the cells in granulomas. Macrophages are suchimportant cells for the development of hepatic granulomas, so it is logical for us tospeculate that the apoptosis of macrophages will markedly impact the development ofthe hepatic granulomas and thereby influence the pathopoiesis of schistosomeinfection.
Our research proved that schistosome infection would induce apoptosis in macrophages, however, we noticed that although the absolute numbers of apoptoticmacrophages apparently increased after schistosome infection, the total numbers ofmacrophages obviously increased and the percentages of apoptotic macrophagesdistinctly decreased, so what contributed to the decreased percentages of apoptoticmacrophages? We found that, cytokine IL-7was dramatically induced to increase thetotal numbers of macrophages by preventing the apoptosis of them. The increasedmacrophages thereby lead to the enhancement of hepatic granulomas, which maycontribute to the Immune pathological damage in liver.
Immediately after that we further explored the mechanisms of the prevention ofmacrophages apoptosis by IL-7. Results turned out that IL-7could signal through theIL-7R(consists of α chain, CD127, and γ chain, CD132) expressed on macrophages toprevent the apoptosis of macrophages and the apoptosis induced by soluble eggantigen(SEA). The function of increasing numbers of macrophages by IL-7was notinfluenced by the changes of macrophages proliferation after IL-7treatment.Different from previous studies which declared that IL-7prevents T cell apoptosis byup-regulating anti-apoptotic members and down-regulating pro-apoptotic members ofBCL-2protein family, our study found that IL-7prevented macrophages apoptosisindependent of BCL-2protein family. The pro-apoptotic members of BCL-2proteinfamily(BAX,BAK) works through promoting the release of cytochrome C andSmac/Diablo from mitochondria to activate caspases and promote apoptosis, whilethe anti-apoptotic members(BCL-2,BCL-XL) works on the contrary. However, BCL-2protein family can still promote or prevent cell apoptosis independent of caspases.This research found that IL-7could prevent macrophages apoptosis independent ofcaspases(but we could not rule out the impact of caspase-dependent pathway yet),and schistosome infection and the egg antigen induced macrophages apoptosis wereindependent of BCL-2protein family and caspases which could be prevented by IL-7 through the same way. Finally, our research indicated that SEA may inducedmacrophages apoptosis by induction of macrophages autophagy, while IL-7justinhibited macrophages autophagy to prevent macrophages apoptosis.
In a word, this research observed for the first time that IL-7could also preventapoptosis of immunocytes (macrophages) other than T cells. And we innovativelyfound that mechanisms underlying in the preventing apoptotic role of IL-7onmacrophages were independent of caspases while through inhibiting autophagy,which was different from previous studies. These results dramatically expanded theexisting reorganization of the preventing apoptotic function of IL-7, and can apply asclinical supervision for the control of hepatic granulomas in schistosomiasis.
引文
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