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<p>Hypothermia is widely acknowledged to exert protective effects against cerebral&#xa0;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 <i>in vitro</i> and <i>in vivo</i>. These findings highlight microglia pyroptosis as a potential therapeutic target to prevent neurodevelopmental impairment in the developing brain following hypothermic hypoxia-ischemia.</p>

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Microglia Pyroptosis-Derived IL-18 Drives White Matter Injury in Developing Brain following Hypothermic Hypoxia-Ischemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月9日

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  • Hongtong Chen,
  • Shengyu Jin,
  • Mingdong Liu,
  • Yifan Zhu,
  • Liren Zhang,
  • Cong Li,
  • Peng Liu,
  • Xiaoping Tong,
  • Zhongqun Zhu

摘要

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.