Role of microglial activation and neuroinflammation in neurotoxicity of acrylamide in vivo and in vitro
Role of microglial activation and neuroinflammation in neurotoxicity of acrylamide in vivo and in vitro
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DOI：
10.1007/s00204-019-02471-0
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发表时间：
2019-05
影响因子：
6.1
通讯作者：
Cai Zong;Rieka Hasegawa;M. Urushitani;Lingyi Zhang;Daichi Nagashima;T. Sakurai;S. Ichihara;S. Ohsako
中科院分区：
文献类型：
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作者：
Cai Zong;Rieka Hasegawa;M. Urushitani;Lingyi Zhang;Daichi Nagashima;T. Sakurai;S. Ichihara;S. Ohsako
丙烯酰胺是一种软亲电试剂，广泛用于工业和实验室，也会污染某些食品。丙烯酰胺的神经毒性和神经退行性作用已在人类和实验动物中报道，尽管其潜在机制尚不清楚。小胶质细胞的激活和神经炎症已经在各种神经退行性疾病以及大脑的其他病理中得到证实。本研究旨在探讨小胶质细胞激活和神经炎症在丙烯酰胺神经毒性中的作用。10周龄雄性Wistar大鼠分别以0、0.2、2、20 mg/kg BW灌胃丙烯酰胺，每天1次，连续5周。结果显示，丙烯酰胺暴露5周后，大鼠大脑皮层出现炎症反应，促炎细胞因子IL-1β、IL-6和IL-18的mRNA和蛋白表达上调。丙烯酰胺还能诱导小胶质细胞活化，表现为小胶质细胞标志物CD11b和CD40表达增加，CD11b/c阳性小胶质细胞面积增加，小胶质细胞过程长度增加。BV-2小胶质细胞的体外研究证实了小胶质细胞的炎症反应，可以通过时间（0-36 h; 50 μM）和剂量（0-500 μM; 24 h）依赖性的IL-1β和IL-18 mRNA表达以及炎症标志物iNOS的增加来证明。此外，丙烯酰胺诱导的促炎细胞因子上调是通过NLRP3炎症小体途径介导的，这可以通过大鼠大脑皮层中NLRP3、caspase 1和ASC的表达增加，以及NLRP3炎症小体抑制剂对丙烯酰胺诱导的BV-2小胶质细胞中NLRP3、caspase 1、IL-1β和IL-18的抑制作用来证明。
Acrylamide, a soft electrophile, is widely used in the industry and laboratories, and also contaminates certain foods. Neurotoxicity and neurodegenerative effects of acrylamide have been reported in humans and experimental animals, although the underlying mechanism remains obscure. Activation of microglia and neuroinflammation has been demonstrated in various neurodegenerative diseases as well as other pathologies of the brain. The present study aimed to investigate the role of microglial activation and neuroinflammation in acrylamide neurotoxicity. Male 10-week-old Wistar rats were exposed to acrylamide by gavage at 0, 0.2, 2, or 20 mg/kg BW, once per day for 5 weeks. The results showed that 5-week exposure to acrylamide induced inflammatory responses in the cerebral cortex, evident by upregulated mRNA and protein expression of pro-inflammatory cytokines IL-1β, IL-6, and IL-18. Acrylamide also induced activation of microglia, indicated by increased expression of microglial markers, CD11b and CD40, and increased CD11b/c-positive microglial area and microglial process length. In vitro studies using BV-2 microglial cells confirmed microglial inflammatory response, as evident by time- (0–36 h; 50 μM) and dose- (0–500 μM; 24 h) dependent increase in mRNA expression of IL-1β and IL-18, as well as the inflammatory marker iNOS. Furthermore, acrylamide-induced upregulation of pro-inflammatory cytokines was mediated through the NLRP3 inflammasome pathway, as evident by increased expression of NLRP3, caspase 1, and ASC in the rat cerebral cortex, and by the inhibitory effects of NLRP3 inflammasome inhibitor on the acrylamide-induced upregulation of NLRP3, caspase 1, IL-1β, and IL-18 in BV-2 microglia.