17β-estradiol alleviated ferroptotic neuroinflammation by suppressing ATF4 in mouse model of Parkinson's disease.

IF 6.1 2区 生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-12-19 DOI:10.1038/s41420-024-02273-z
Guoming Wang, Wenxin Zhuang, Yijun Zhou, Xu Wang, Zhenfeng Li, Chuanliang Liu, Wentong Li, Maotao He, E Lv
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Abstract

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.

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17β-雌二醇通过抑制ATF4减轻帕金森病小鼠模型的紧铁性神经炎症。
由小胶质细胞激活引起的神经炎症是帕金森病(PD)进展的重要因素,新证据表明铁下沉在小胶质细胞激活和随后的多巴胺能神经元丢失中起关键作用。然而,铁下垂导致PD的基本发病机制尚不清楚。基于GEO数据集,PD患者和PD MPTP小鼠模型中发现富铁下垂相关基因,其中ATF4显著差异表达。在我们的研究中,ATF4的异位表达增强了MPP+-诱导的细胞毒性和BV2细胞的活化,上调了细胞内L-ROS、TLR4和pNF-κB。异位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,ATF4的沉默可增强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,E2进一步降低ATF4的表达,抑制促炎细胞因子的表达和TLR4/NF-κB通路的激活。综上所述,E2通过抑制ATF4有效抵消TLR4/NF-κB信号通路,抑制铁下垂引发的炎症反应,最终发挥抗pd作用。
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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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