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

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.