Neutrophil Mobilization Triggers Microglial Functional Change to Exacerbate Cerebral Ischemia‐Reperfusion Injury

Abstract Acute ischemic stroke is a leading cause of mortality and disability worldwide. Neuroinflammation following ischemia‐reperfusion plays a critical role in the disease's pathogenesis. Neutrophil aggregation and clearance within the brain parenchyma influence neuroinflammatory damage during ischemic stroke. Microglia‐mediated phagocytosis plays a pivotal role in mitigating neuroinflammation and promoting brain parenchyma recovery. However, the mechanisms underlying the cross‐talk between neutrophils and microglia remain poorly understood. Here, this study demonstrates that neutrophils can trigger microglial functional change to inhibit microglial phagocytosis and promote pyroptosis, which is regulated by neutrophil‐derived myeloid‐related protein 14. Additionally, interleukin‐1 β released by pyroptotic microglia further upregulates myeloid‐related protein 14 expression and facilitates neutrophil mobilization from the bone marrow, establishing a self‐sustaining inflammatory loop. Therefore, neutrophils accumulate in the brain parenchyma and further exacerbate microglial neuroinflammation in the ischemic brain. These findings reveal a previously unknown interaction between neutrophils and microglia after acute ischemic stroke and suggest that targeting myeloid‐related protein 14 may provide a novel therapeutic strategy for ischemic stroke therapy.