Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
School of Resources and Environment, Northeast Agricultural University, Harbin 150030, PR China.
Sci Total Environ. 2020 May 1;715:136942. doi: 10.1016/j.scitotenv.2020.136942. Epub 2020 Jan 25.
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 AlCl for 90 days. The open-field test results showed that AlCl caused depressive behavior in rats. Histopathological evidence showed that AlCl induced 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 AlCl induced 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 AlCl, while <150 mg/kg AlCl tended to induce apoptosis. Finally, AlCl increased the proteins level of IL-1β, IL-1RI, IL-1RAcP, JNK and p-JNK, indicating that AlCl activated 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 AlCl. Thus, we concluded that AlCl induced hippocampal neural cells death and depression-like behavior in rats by activating IL-1β/JNK signaling pathway.
铝（Al）是一种无机污染物，可诱导神经细胞凋亡和坏死，从而导致抑郁和神经退行性疾病。IL-1β/JNK 信号通路可以调节细胞凋亡和坏死。然而，IL-1β/JNK 信号通路是否参与调节铝诱导的海马神经细胞凋亡和坏死尚不清楚。为了研究铝对神经细胞凋亡和坏死的作用机制，将大鼠经口暴露于不同剂量的 AlCl3 中 90 天。旷场试验结果表明，AlCl3 导致大鼠出现抑郁行为。组织病理学证据表明，AlCl3 诱导海马神经细胞凋亡和坏死。此外，Bax/Bcl-2 mRNA 表达比值、caspase-3 活性和 mRNA 表达以及 TUNEL 阳性率升高，同时 TNF-α mRNA 和蛋白表达水平、TNFR1、RIP1、RIP3 和 MLKL 蛋白水平升高，而 caspase-8 蛋白水平降低在暴露于 Al 的大鼠海马区。这些结果证明 AlCl3 诱导海马神经细胞凋亡和坏死。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（450mg/kg）AlCl3 下更可能发生坏死，而 <150mg/kg AlCl3 则倾向于诱导凋亡。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，应用 IL-1 受体拮抗剂（IL-1Ra）抑制了 AlCl3 引起的 JNK 磷酸化和凋亡及坏死相关基因的表达。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。
