Apoptosis and necroptosis of mouse hippocampal and parenchymal astrocytes, microglia and neurons caused by Angiostrongylus cantonensis infection.
Apoptosis and necroptosis of mouse hippocampal and parenchymal astrocytes, microglia and neurons caused by Angiostrongylus cantonensis infection.
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广州管圆线虫感染引起的小鼠海马和实质星形胶质细胞、小胶质细胞和神经元的凋亡和坏死性凋亡
DOI：
10.1186/s13071-017-2565-y
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发表时间：
2017-12-19
影响因子：
3.2
通讯作者：
Zhiyue L
中科院分区：
文献类型：
--
作者：
Mengying Z;Yiyue X;Tong P;Yue H;Limpanont Y;Ping H;Okanurak K;Yanqi W;Dekumyoy P;Hongli Z;Watthanakulpanich D;Zhongdao W;Zhi W;Zhiyue L
广州管圆线虫是管圆线虫科中唯一导致以嗜酸性粒细胞性脑膜炎或脑膜脑炎为特征的人类中枢神经系统感染的寄生虫。广州管圆线虫幼虫导致宿主广泛神经损伤的机制仍不清楚。本研究的目的是研究广州管圆线虫感染小鼠大脑中的细胞凋亡、坏死性凋亡和自噬，这对于更好地理解广州管圆线虫病的发病机制具有重要价值。
分别通过莫里斯水迷宫试验和苏木精 - 伊红（H&E）染色检测广州管圆线虫感染小鼠脑组织的功能和组织学神经损伤。通过实时定量聚合酶链反应（RT - PCR）对细胞凋亡、坏死性凋亡和自噬相关基因的转录和翻译水平进行定量，并通过蛋白质印迹和免疫组织化学（IHC）分析进行评估。通过流式细胞术和透射电子显微镜（TEM）分析感染脑组织中的凋亡和坏死性凋亡细胞及其分布。
随着广州管圆线虫感染的进展，中枢神经系统的炎症反应恶化，其特征是脑膜下有大量炎症细胞浸润，在感染后21天（dpi）达到峰值。小鼠在14 dpi时学习和记忆能力显著下降，表明其认知功能明显受损。与对照组相比，caspase - 3、 - 4、 - 6和RIP3的mRNA水平以及caspase - 4、切割后的caspase - 3、切割后的caspase - 6、RIP3和pRIP3的蛋白质水平明显升高。然而，FADD、Beclin - 1或LC3B的mRNA或蛋白质水平没有明显变化，这表明广州管圆线虫感染小鼠的脑组织中发生了细胞凋亡和坏死性凋亡，但没有发生自噬。实时定量RT - PCR、蛋白质印迹、IHC、流式细胞术和TEM结果进一步揭示了感染小鼠脑实质和海马区的凋亡和坏死性小胶质细胞、星形胶质细胞和神经元。
据我们所知，我们首次表明广州管圆线虫感染导致宿主脑组织脑实质和海马区的小胶质细胞和星形胶质细胞发生细胞凋亡和坏死性凋亡，进一步阐明了广州管圆线虫感染的发病机制，并为广州管圆线虫病的治疗提供了潜在的治疗靶点。
Background:Angiostrongylus cantonensis has been the only parasite among Angiostrongylidae to cause human central nervous system infection characterized by eosinophilic meningitis or meningoencephalitis. The mechanism of the extensive neurological impairments of hosts caused by A. cantonensis larvae remains unclear. The aim of the present study was to investigate apoptosis, necroptosis and autophagy in the brains of mice infected with A. cantonensis, which will be valuable for better understanding the pathogenesis of angiostrongyliasis cantonensis.Methods:Functional and histological neurological impairments of brain tissues from mice infected with A. cantonensis were measured by the Morris water maze test and haematoxylin and eosin (H&E) staining, respectively. The transcriptional and translational levels of apoptosis-, necroptosis- and autophagy-related genes were quantified by quantitative real-time polymerase chain reaction (RT-PCR), and assessed by western blot and immunohistochemistry (IHC) analysis. Apoptotic and necroptotic cells and their distributions in infected brain tissues were analysed by flow cytometry and transmission electron microscopy (TEM).Results:Inflammatory response in the central nervous system deteriorated as A. cantonensis infection evolved, as characterized by abundant inflammatory cell infiltration underneath the meninges, which peaked at 21 days post-infection (dpi). The learning and memory capacities of the mice were significantly decreased at 14 dpi, indicating prominent impairment of their cognitive functions. Compared with those of the control group, the mRNA levels of caspase-3, -4, -6, and RIP3 and the protein levels of caspase-4, cleaved caspase-3, cleaved caspase-6, RIP3, and pRIP3 were obviously elevated. However, no changes in the mRNA or protein levels of FADD, Beclin-1 or LC3B were evident, indicating that apoptosis and necroptosis, but not autophagy, occurred in the brain tissues of mice infected with A. cantonensis. The quantitative RT-PCR, western blot, IHC, flow cytometry and TEM results further revealed the apoptotic and necroptotic microglia, astrocytes and neurons in the parenchymal and hippocampal regions of infected mice.Conclusions:To our knowledge, we showed for the first time that A. cantonensis infection causes the apoptosis and necroptosis of microglia and astrocytes in the parenchymal and hippocampal regions of host brain tissues, further demonstrating the pathogenesis of A. cantonensis infection and providing potential therapeutic targets for the management of angiostrongyliasis.
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