Ferroptosis contributes to JEV-induced neuronal damage and neuroinflammation

Wenjing Zhu; Qi Li; Yong Yin; Huanchun Chen; Youhui Si; Bibo Zhu; Shengbo Cao; Zikai Zhao; Jing Ye

doi:10.1016/j.virs.2023.12.004

February 2024

. doi: 10.1016/j.virs.2023.12.004

Citation: Wenjing Zhu, Qi Li, Yong Yin, Huanchun Chen, Youhui Si, Bibo Zhu, Shengbo Cao, Zikai Zhao, Jing Ye. Ferroptosis contributes to JEV-induced neuronal damage and neuroinflammation .VIROLOGICA SINICA, 2024, 39(1) : 144-155. http://dx.doi.org/10.1016/j.virs.2023.12.004

铁死亡促进日本脑炎病毒引起的神经元损伤和神经炎症

朱文静 ^a,b,c,d ,
李琦 ^a,b,c,d ,
殷勇 ^a,b,c,d ,
陈焕春 ^a,b,c,d ,
司有辉 ^a,b,c,d ,
朱碧波 ^a,b,c,d ,
曹胜波 ^a,b,c,d ,
赵子恺 ^a,b,c,d,, ,
叶静 ^a,b,c,d,,

a. 华中农业大学, 农业微生物资源发掘与利用全国重点实验室;
b. 华中农业大学, 动物育种与健康养殖前沿科学中心;
c. 华中农业大学, 生猪健康养殖协同创新中心;
d. 华中农业大学, 湖北洪山实验室

通讯作者： 赵子恺, zkzhao@mail.hzau.edu.cn; 叶静, yej@mail.hzau.edu.cn
收稿日期： 2023-05-13
录用日期： 2023-12-13

摘要

铁死亡是一种新发现的、由铁依赖性脂质过氧化驱动的程序性细胞死亡方式，与多种器官损伤和退行性病变过程有关。尽管研究表明多种细胞死亡方式参与日本脑炎病毒（JEV）感染引起的神经炎症和神经元损伤，但目前尚不清楚铁死亡是否参与其中。在本研究中，我们在体外和体内模型中发现了JEV感染能够引起神经元铁死亡。结果表明，JEV感染通过抑制GSH/GPX4介导的抗氧化系统的功能，并通过促进YAP1/ACSL4介导的脂质过氧化来诱导神经元铁死亡。进一步的分析表明，JEV的C和prM蛋白在此过程中发挥重要作用。此外，本研究通过小鼠感染模型证明使用铁死亡抑制剂能够降低JEV感染小鼠脑中的病毒滴度和炎症反应，并提高感染小鼠的存活率。本研究揭示了铁死亡在JEV致病中的关键作用，并为病毒性脑炎的预防和治疗提供了新的思路。
- 日本脑炎病毒
- , 铁死亡
- , 神经元
- , 脂质过氧化
- , 炎症反应

Ferroptosis contributes to JEV-induced neuronal damage and neuroinflammation

Wenjing Zhu ^a,b,c,d ,
Qi Li ^a,b,c,d ,
Yong Yin ^a,b,c,d ,
Huanchun Chen ^a,b,c,d ,
Youhui Si ^a,b,c,d ,
Bibo Zhu ^a,b,c,d ,
Shengbo Cao ^a,b,c,d ,
Zikai Zhao ^a,b,c,d,, ,
Jing Ye ^a,b,c,d,,

a. National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China;
b. Frontiers Science Center for Animal Breeding and Sustainable Production, Huazhong Agricultural University, Wuhan, 430070, China;
c. The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China;
d. Hubei Hongshan Laboratory, Wuhan, 430070, China

Corresponding author: Zikai Zhao, zkzhao@mail.hzau.edu.cn Jing Ye, yej@mail.hzau.edu.cn
Received Date: 13 May 2023
Accepted Date: 13 December 2023

Abstract

Ferroptosis is a newly discovered prototype of programmed cell death (PCD) driven by iron-dependent phospholipid peroxidation accumulation, and it has been linked to numerous organ injuries and degenerative pathologies. Although studies have shown that a variety of cell death processes contribute to JEV-induced neuroinflammation and neuronal injury, there is currently limited research on the specific involvement of ferroptosis. In this study, we explored the neuronal ferroptosis induced by JEV infection in vitro and in vivo. Our results indicated that JEV infection induces neuronal ferroptosis through inhibiting the function of the antioxidant system mediated by glutathione (GSH)/glutathione peroxidase 4 (GPX4), as well as by promoting lipid peroxidation mediated by yes-associated protein 1 (YAP1)/long-chain acyl-CoA synthetase 4 (ACSL4). Further analyses revealed that JEV E and prM proteins function as agonists, inducing ferroptosis. Moreover, we found that treatment with a ferroptosis inhibitor in JEV-infected mice reduces the viral titers and inflammation in the mouse brains, ultimately improving the survival rate of infected mice. In conclusion, our study unveils a critical role of ferroptosis in the pathogenesis of JEV, providing new ideas for the prevention and treatment of viral encephalitis.
- Japanese encephalitis virus (JEV)
- , Ferroptosis
- , Neuron
- , Lipid peroxidation
- , Inflammatory response

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