Neurotoxic A1 astrocytes promote neuronal ferroptosis via CXCL10/CXCR3 axis in epilepsy

Peiyu Liang; Xinyi Zhang; Yahui Zhang; Yifan Wu; Yinghao Song; Xueyang Wang; Taoxiang Chen; Wanhong Liu; Biwen Peng; Jun Yin; Fanggang He; Yuanteng Fan; Song Han; Xiaohua He

doi:10.1016/j.freeradbiomed.2023.01.002

Neurotoxic A1 astrocytes promote neuronal ferroptosis via CXCL10/CXCR3 axis in epilepsy

Free Radic Biol Med. 2023 Feb 1:195:329-342. doi: 10.1016/j.freeradbiomed.2023.01.002. Epub 2023 Jan 5.

Authors

Peiyu Liang¹, Xinyi Zhang¹, Yahui Zhang¹, Yifan Wu¹, Yinghao Song¹, Xueyang Wang¹, Taoxiang Chen², Wanhong Liu², Biwen Peng², Jun Yin³, Fanggang He⁴, Yuanteng Fan⁵, Song Han⁶, Xiaohua He⁷

Affiliations

¹ Department of Pathophysiology, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
² Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
³ Department of Pathophysiology, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
⁴ Institute of Forensic Medicine, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
⁵ Department of Neurology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China. Electronic address: fanyuanteng@163.com.
⁶ Department of Pathophysiology, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, China. Electronic address: hansong@whu.edu.cn.
⁷ Department of Pathophysiology, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, China. Electronic address: hexiaohua@whu.edu.cn.

PMID: 36610561
DOI: 10.1016/j.freeradbiomed.2023.01.002

Abstract

Epilepsy is a common neurological disorder with a complex etiology. Ferroptosis, a new form of programmed cell death, is characterized by the accumulation of lipid peroxides and associated with seizures. However, the underlying mechanism of ferroptosis in epilepsy remains elusive. Here, we found that GPX4-GSH-dependent neuronal ferroptosis was detected in epileptic mice, which was attenuated with ferroptosis inhibitors. Moreover, activated neurotoxic A1 astrocytes facilitated seizure-related neuronal ferroptosis in epileptic brains. Inhibition of ferroptosis blocked A1 astrocyte-induced neurotoxicity. A1 astrocyte-secreted CXCL10 enhanced STAT3 phosphorylation but suppressed SLC7A11 in neurons via CXCR3, leading to ferroptosis-associated lipid peroxidation in a GPX4-dependent manner. This was in line with clinical findings, showing a significant correlation between neuronal ferroptosis and A1 astrocytes in epileptic patients. In summary, the present data show that A1 astrocyte-induced neuronal ferroptosis contributes to the pathogenesis of epilepsy, which offers a novel therapeutic target for precision medicine.

Keywords: A1 astrocyte; CXCL10; Epilepsy; Ferroptosis; Lipid peroxidation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Astrocytes / metabolism
Epilepsy* / genetics
Epilepsy* / metabolism
Ferroptosis* / genetics
Mice
Neurons / metabolism