Hongtong Chen1  · Shengyu Jin2,3,4 · Mingdong Liu3,5 · Yifan Zhu1  · Liren Zhang6  · Cong Li1  · Peng Liu4  · Xiaoping Tong2,3,4  · Zhongqun Zhu1

1 Department of Cardiothoracic Surgery, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China 

2 Department of Obstetrics and Gynecology, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China 

3 Department of Anatomy and Physiology, School of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 201318, China 

4 Key Laboratory of Molecular Neurobiology, Ministry of Education, Navy Military Medical University, Shanghai 200433, China 

5 Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou 510623, China 

6 Department of Neurology, Changhai Hospital, Naval Medical University, Shanghai 200433, China

Abstract

Hypothermia is widely acknowledged to exert protective effects against cerebral hypoxic-ischemic injury. Despite the neuroprotective effects of hypothermia, the developing brain remains vulnerable to white matter injury (WMI) during hypothermic hypoxia-ischemia, potentially disrupting neurodevelopment and leading to long-term neurological deficits. However, the mechanisms underlying WMI and effective therapeutic strategies following hypothermic hypoxia-ischemia in the developing brain are not well understood. Our study demonstrates that microglia experience pyroptosis following hypothermic hypoxia-ischemia. The release of interleukin 18 (IL-18) derived from pyroptotic microglia induces mature oligodendrocyte death and axonal demyelination, resulting in WMI. Pharmacological inhibition of pyroptosis with disulfiram (DSF) significantly alleviates WMI in vitro and in vivo. These findings highlight microglia pyroptosis as a potential therapeutic target to prevent neurodevelopmental impairment in the developing brain following hypothermic hypoxia-ischemia.

Keywords

Microglia; Pyroptosis; White matter injury; Hypothermic hypoxia-ischemia

[SpringerLink]