Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
Department of Encephalopathy, Traditional Chinese Medicine Hospital of Haian County Affiliated Hospital, Nanjing University of Chinese Medicine of Hanlin College, Nantong, Jiangsu 226600, People's Republic of China.
Neurotoxicology. 2018 Jan;64:195-203. doi: 10.1016/j.neuro.2017.04.001. Epub 2017 Apr 4.
Chronic manganese (Mn) exposure can lead to neuroinflammation and neurological deficit, which resemble idiopathic Parkinson's disease (IPD). However, the precise mechanisms underlying Mn exposure-induced neurotoxicity remain incompletely understood. Microglia can become hyperactivated and plays a vital role in neuroinflammation and consequent neurodegeneration in response to pro-inflammatory stimuli. In the present study, we found that HAPI microglial cells exhibited increased secretion of pro-inflammatory TNF-α and IL-1β following Mn exposure in dose- and time-dependent manners. In addition, we showed that Mn exposure could trigger the activation of JAK2/STAT3 signaling pathway in microglia. Notably, Mn-induced secretion of TNF-α and IL-1β was significantly attenuated by the treatment of JAK2 inhibitor. Finally, through incubating PC12 neuronal cells with Mn-treated microglial conditioned medium, we demonstrated that Mn-induced secretion of microglial TNF-α and IL-1β facilitated neuronal apoptosis. Thus, we speculate that Mn exposure might trigger JAK2-STAT3 signal pathway in microglia, leading to resultant neuroinflammation and neuronal loss.
慢性锰（Mn）暴露可导致神经炎症和神经功能缺损，类似于特发性帕金森病（IPD）。然而，Mn 暴露诱导的神经毒性的确切机制仍不完全清楚。小胶质细胞可被过度激活，并在对促炎刺激的反应中发挥重要作用，导致神经炎症和随后的神经退行性变。在本研究中，我们发现 HAPI 小胶质细胞在 Mn 暴露后以剂量和时间依赖的方式表现出促炎细胞因子 TNF-α 和 IL-1β 的分泌增加。此外，我们表明 Mn 暴露可触发小胶质细胞中 JAK2/STAT3 信号通路的激活。值得注意的是，JAK2 抑制剂处理可显著减轻 Mn 诱导的 TNF-α 和 IL-1β 的分泌。最后，通过将 Mn 处理的小胶质细胞条件培养基孵育到 PC12 神经元细胞中，我们证明了 Mn 诱导的小胶质细胞 TNF-α 和 IL-1β 的分泌促进了神经元凋亡。因此，我们推测 Mn 暴露可能会在小胶质细胞中触发 JAK2-STAT3 信号通路，导致神经炎症和神经元丢失。
