Zhang Chengzhi, Yang Yanmei, Gao Yanhui, Sun Dianjun
Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
Toxicology. 2022 Mar 15;469:153132. doi: 10.1016/j.tox.2022.153132. Epub 2022 Feb 13.
Excessive fluoride exposure can induce neuron apoptosis that is associated with neurodegenerative changes, but the mechanisms remain elusive. It has been suggested that chronic fluoride-induced microglia activation contributes to neuronal damage by producing pro-inflammatory cytokines. IL-1β, a pro-inflammatory cytokine released by activated microglia, is capable of inducing JNK phosphorylation and is associated with neurodegenerative diseases. In the current study, in vivo results demonstrate that excessive NaF impaired spatial learning and memory ability, microglia activation, and up-regulation of IL-1β in rats. Moreover, NaF exposure induced JNK pathway activation and associated apoptosis. These results were validated in vitro: NaF could induce BV-2 microglia cell activation and increase the concentration of IL-1β in the culture medium. When PC-12 cells were cultured with BV-2 CM or IL-1β for 24 h, the viability of PC-12 cells decreased, with enhanced apoptosis. In addition, IL-1 receptor antagonist (IL-1Ra) or SP600125 (JNK pathway inhibitor) diminished the IL-1β-induced activation of JNK pathway-mediated neuron apoptosis. Therefore, our study demonstrates that the IL-1β/JNK signaling pathway is involved in NaF-induced apoptosis of hippocampal neurons and cognitive dysfunction.
过量氟暴露可诱导与神经退行性变相关的神经元凋亡，但其机制仍不清楚。有人提出，慢性氟诱导的小胶质细胞活化通过产生促炎细胞因子导致神经元损伤。IL-1β是活化小胶质细胞释放的一种促炎细胞因子，能够诱导JNK磷酸化，并与神经退行性疾病有关。在本研究中，体内实验结果表明，过量的氟化钠损害大鼠的空间学习和记忆能力、小胶质细胞活化以及IL-1β的上调。此外，氟化钠暴露诱导JNK通路活化和相关的细胞凋亡。这些结果在体外得到验证：氟化钠可诱导BV-2小胶质细胞活化，并增加培养基中IL-1β的浓度。当PC-12细胞与BV-2条件培养基或IL-1β共培养24小时时，PC-12细胞的活力下降，细胞凋亡增加。此外，IL-1受体拮抗剂（IL-1Ra）或SP600125（JNK通路抑制剂）可减少IL-1β诱导的JNK通路介导的神经元凋亡。因此，我们的研究表明，IL-1β/JNK信号通路参与了氟化钠诱导的海马神经元凋亡和认知功能障碍。
