Wang Guoming, Zhuang Wenxin, Zhou Yijun, Wang Xu, Li Zhenfeng, Liu Chuanliang, Li Wentong, He Maotao, Lv E
School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China.
Experimental Center for Medical Research, Shandong Second Medical University, Weifang, Shandong Province, China.
Cell Death Discov. 2024 Dec 19;10(1):507. doi: 10.1038/s41420-024-02273-z.
Neuroinflammation induced by activation of microglial is a vital contributor to progression of Parkinson's disease (PD), emerging evidences suggested that ferroptosis played a pivotal role in microglial activation and subsequent dopaminergic neuron loss. Nevertheless, the fundamental pathogenesis of that ferroptosis contributes to PD is not yet sufficiently understood. Based on GEO dataset, ferroptosis related genes were found to be enriched in PD patients and MPTP mouse model of PD, among them, ATF4 was found to be dramatically differentially expressed. In our study, ectopic expression of ATF4 augmented MPP-induced cytotoxic and activation of BV2 cells with upregulated intracellular L-ROS, TLR4 and pNF-κB. Ectopic ATF4 effectively promoted transformation of microglial into M1 pro-inflammatory phenotype. 17β-estradiol (E2) attenuated expression of ATF4 in BV2 cells, silence of ATF4 enhanced protective effect of E2 on MPP-treated BV2 cells. In MPTP-induced PD mouse model, administration of E2 further abated expression of ATF4 and inhibited expressions of pro-inflammatory cytokines and activation of TLR4/NF-κB pathway. Overall, E2 effectively counteracted TLR4/NF-κB signaling pathway by restraining ATF4 and inhibited inflammatory response triggered by ferroptosis, ultimately exerted anti-PD effects.
小胶质细胞激活诱导的神经炎症是帕金森病（PD）进展的重要因素，新出现的证据表明，铁死亡在小胶质细胞激活及随后的多巴胺能神经元丢失中起关键作用。然而，铁死亡导致PD的基本发病机制尚未得到充分理解。基于基因表达综合数据库（GEO）数据集，发现铁死亡相关基因在PD患者和MPTP诱导的PD小鼠模型中富集，其中，发现激活转录因子4（ATF4）有显著差异表达。在我们的研究中，ATF4的异位表达增强了1-甲基-4-苯基吡啶离子（MPP）诱导的BV2细胞毒性及细胞内活性氧（L-ROS）、Toll样受体4（TLR4）和磷酸化核因子κB（pNF-κB）的激活。异位表达的ATF4有效促进小胶质细胞向M1促炎表型转化。17β-雌二醇（E2）可减弱BV2细胞中ATF4的表达，敲低ATF4可增强E2对MPP处理的BV2细胞的保护作用。在MPTP诱导的PD小鼠模型中，给予E2可进一步降低ATF4的表达，并抑制促炎细胞因子的表达及TLR4/核因子κB（NF-κB）信号通路的激活。总体而言，E2通过抑制ATF4有效对抗TLR4/NF-κB信号通路，并抑制铁死亡引发的炎症反应，最终发挥抗PD作用。
