Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1 beta/JNK signaling pathway
Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1 beta/JNK signaling pathway
复制标题
三氯化铝通过激活IL-1β/JNK信号通路导致大鼠海马神经细胞死亡并随后出现抑郁样行为
DOI：
10.1016/j.scitotenv.2020.136942
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发表时间：
2020
影响因子：
9.8
通讯作者：
Fan Honggang
中科院分区：
文献类型：
--
作者：
Zhang Haiyang;Wei Mian;Lu Xiangyu;Sun Qinghong;Wang Chuqiao;Zhang Jiuyan;Fan Honggang
铝（Al）是一种无机污染物，可诱导神经细胞凋亡和坏死性凋亡，从而引起抑郁症和神经退行性疾病。 IL-1β/JNK信号通路可调节细胞凋亡和坏死性凋亡。然而，IL-1β/JNK信号通路是否参与Al诱导的海马神经细胞凋亡和坏死性凋亡的调节尚不清楚。为了研究Al对神经细胞凋亡和坏死性凋亡的机制，大鼠口服不同剂量的AlCl3 90天。旷场试验结果显示AlCl3引起大鼠抑郁行为。组织病理学证据表明AlCl3诱导海马神经细胞凋亡和坏死。 Al暴露组海马Bax/Bcl-2 mRNA表达比值、caspase-3活性和mRNA表达量及TUNEL阳性率均上调,TNF-α mRNA和蛋白表达水平,TNFR1、RIP1、RIP3和MLKL蛋白水平升高,caspase-8蛋白水平降低。这些结果证明AlCl3诱导海马神经细胞凋亡和坏死性凋亡。结合组织病理学和相关性分析，我们推断海马神经细胞在高剂量（450 mg/kg）AlCl3下更容易发生坏死性凋亡，而<150 mg/kg AlCl3倾向于诱导细胞凋亡。最后，AlCl3增加了IL-1β、IL-1RI、IL-1RAcP、JNK和p-JNK的蛋白水平，表明AlCl3激活了IL-1β/JNK信号通路。然而，IL-1受体拮抗剂(IL-1Ra)的应用抑制了JNK的磷酸化以及AlCl3引起的细胞凋亡和坏死性凋亡相关基因的表达。因此，我们得出结论，AlCl3通过激活IL-1β/JNK信号通路诱导大鼠海马神经细胞死亡和抑郁样行为。
Aluminum (Al) is an inorganic pollutant that induces nerve cells apoptosis and necroptosis, thereby causing depression and neurodegenerative diseases. IL-1β/JNK signaling pathway can regulate apoptosis and necroptosis. However, it remains unclear whether IL-1β/JNK signaling pathway is involving in the regulation of Al-induced hippocampal neural cells apoptosis and necroptosis. To investigate the mechanism of Al on neural cells apoptosis and necroptosis, rats were orally exposed to different doses of AlCl3for 90 days. The open-field test results showed that AlCl3caused depressive behavior in rats. Histopathological evidence showed that AlCl3induced hippocampal neural cells apoptosis and necrosis. Moreover, Bax/Bcl-2 mRNA expression ratio, caspase-3 activity and mRNA expression and TUNEL positive rates were upregulated, meanwhile, TNF-α mRNA and protein expression levels, TNFR1, RIP1, RIP3 and MLKL proteins levels were increased, while caspase-8 protein level was decreased in the hippocampus of Al-exposed groups. These results proved that AlCl3induced hippocampal neural cells apoptosis and necroptosis. Combined with histopathology and correlation analysis, we deduced that hippocampal neural cells were more likely to undergo necroptosis at high doses (450 mg/kg) of AlCl3, while <150 mg/kg AlCl3tended to induce apoptosis. Finally, AlCl3increased the proteins level of IL-1β, IL-1RI, IL-1RAcP, JNK and p-JNK, indicating that AlCl3activated IL-1β/JNK signaling pathway. However, the application of IL-1 receptor antagonist (IL-1Ra) inhibited the phosphorylation of JNK and the related genes expression of apoptosis and necroptosis caused by AlCl3. Thus, we concluded that AlCl3induced hippocampal neural cells death and depression-like behavior in rats by activating IL-1β/JNK signaling pathway.