Medical School of Chinese PLA: Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, China; Department of Neurology, The Second Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China.
Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
Food Chem Toxicol. 2022 May;163:112951. doi: 10.1016/j.fct.2022.112951. Epub 2022 Apr 1.
Excessive manganese (Mn) exposure gives rise to various neurological disorders, including motor dysfunction and cognitive impairment. Microglia-mediated neuroinflammation plays an essential role in the pathogenesis of Mn neurotoxicity. However, the underlying mechanisms have not been fully clarified. Immunoproteasome is a specialized proteasome. Recent studies have shown that immunoproteasome, especially catalytic subunit PSMB8, is highly associated with various neurological diseases. Whether PSMB8 is involved in Mn-neurotoxicity is still unknown. In this study, in vivo and in vitro models were established, and our data showed that Mn exposure upregulated the expression and activity of PSMB8. Selective inhibition of PSMB8 mitigated neuroinflammation with reduced microglial activation and fewer TNF-α, iNOS, and CCL12 production in Mn-treated mice and BV2 cells. Learning and memory tests and Golgi staining further confirmed that inhibition of PSMB8 alleviated Mn-induced recognition memory impairments and synapse deficits. Besides, we found that blocking of PERK signaling inhibited Mn-induced elevation of PSMB8. And inhibition of PSMB8 reduced the phosphorylation of NF-κB p65. Together, our data demonstrated that PSMB8 played an essential role in microglia-mediated neuroinflammation upon Mn exposure, and the underlying mechanisms may be via PERK/NF-κB pathways. These results provide a novel target for the prevention and treatment of Mn-neurotoxicity.
过量的锰（Mn）暴露会导致各种神经紊乱，包括运动功能障碍和认知障碍。小胶质细胞介导的神经炎症在 Mn 神经毒性的发病机制中起着至关重要的作用。然而，其潜在机制尚未完全阐明。免疫蛋白酶体是一种特殊的蛋白酶体。最近的研究表明，免疫蛋白酶体，特别是催化亚基 PSMB8，与各种神经疾病高度相关。PSMB8 是否参与 Mn 神经毒性尚不清楚。在本研究中，建立了体内和体外模型，我们的数据表明，Mn 暴露上调了 PSMB8 的表达和活性。在 Mn 处理的小鼠和 BV2 细胞中，选择性抑制 PSMB8 减轻了神经炎症，减少了小胶质细胞的激活和 TNF-α、iNOS 和 CCL12 的产生。学习和记忆测试和高尔基染色进一步证实，抑制 PSMB8 缓解了 Mn 诱导的识别记忆障碍和突触缺陷。此外，我们发现阻断 PERK 信号抑制了 Mn 诱导的 PSMB8 升高。并且抑制 PSMB8 降低了 NF-κB p65 的磷酸化。总之，我们的数据表明，PSMB8 在 Mn 暴露时在小胶质细胞介导的神经炎症中起着重要作用，其潜在机制可能是通过 PERK/NF-κB 途径。这些结果为 Mn 神经毒性的预防和治疗提供了一个新的靶点。
