Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, Jiangsu, 211166, China.
Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
Toxicol Lett. 2020 Oct 15;333:150-158. doi: 10.1016/j.toxlet.2020.07.028. Epub 2020 Aug 5.
Methamphetamine (Meth), a highly addictive drug, can induce irreversible neuronal damage and cause neuropsychiatric and cognitive disorders. Meth's effects on modulating microglial neuroimmune functions and eliciting neuroinflammation have attracted considerable attention in recent years. Recent evident of the effect of the non-dependent domain containing adaptor inducing interferon (TRIF)/Pellino1 (Peli1) signaling axis on pro-inflammatory cytokine production provides novel clues for inflammation. Therefore, our study investigated Meth-induced neurotoxicity from a neuropathological perspective by examining TLR4-TRIF-Peli1 axis signaling activation. Meth significantly activated microglia accompanied by marked increase of TLR4 and TRIF expression, NF-kB and MAPK pathways activation and the production of IL-1β, TNF-α and IL-6. Peli1 was involved in Meth-mediated neuroinflammation and knockdown of Peli1 strongly reversed NF-kB and MAPK pathways activation and pro-inflammatory cytokine excretion. Intriguingly, Peli1 upregulation induced by Meth was dependent on TRIF rather than the myloid differentiation factor 88 (MyD88) pathway, since the silencing of TRIF significantly suppressed Meth-induced Peli1 upregulation, while MyD88 knockdown had no obvious impact. Additionally, an in vivo study verified TLR4-TRIF-Peli1 axis activation and an enhanced level of downstream cytokine expression in the cortex after Meth treatment. Therefore, these findings provide new insight regarding the specific contributions of the TRIF-Peli1 pathway to Meth-mediated neuroinflammation.
甲基苯丙胺（冰毒）是一种高度成瘾的毒品，可导致不可逆转的神经元损伤，并引起神经精神和认知障碍。近年来，冰毒对调节小胶质细胞神经免疫功能和引发神经炎症的作用引起了相当大的关注。最近有证据表明，干扰素（TRIF）/Pellino1（Peli1）信号轴非依赖结构域衔接蛋白的作用可促进前炎症细胞因子的产生，为炎症提供了新的线索。因此，我们从神经病理学角度研究了冰毒诱导的神经毒性，通过检测 TLR4-TRIF-Peli1 轴信号激活。冰毒显著激活小胶质细胞，伴随着 TLR4 和 TRIF 表达的显著增加、NF-kB 和 MAPK 通路的激活以及 IL-1β、TNF-α 和 IL-6 的产生。Peli1 参与了冰毒介导的神经炎症，而 Peli1 的敲低强烈逆转了 NF-kB 和 MAPK 通路的激活和前炎症细胞因子的释放。有趣的是，冰毒诱导的 Peli1 上调依赖于 TRIF，而不是髓样分化因子 88（MyD88）途径，因为 TRIF 的沉默显著抑制了冰毒诱导的 Peli1 上调，而 MyD88 的敲低没有明显影响。此外，体内研究证实了 TLR4-TRIF-Peli1 轴在冰毒处理后大脑皮层中的激活以及下游细胞因子表达水平的增强。因此，这些发现为 TRIF-Peli1 途径在冰毒介导的神经炎症中的特定作用提供了新的见解。
