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Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke

전한울

2024년 10월 25일

    전체요약: CMPK2를 억제하거나 CMPK2 억제제인 nordihydroguaiaretic acid를 사용하면 쥐에서 허혈성 뇌손상이 감소함

    Highlights
    • CMPK2 expression is increased in microglia/macrophages after ischemic stroke
    • CMPK2 knockdown in microglia/macrophages ameliorates ischemic injury in mice
    • CMPK2 inhibitor nordihydroguaiaretic acid ameliorates ischemic injury in mice

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791%2824%2900191-5

Highlights

•CMPK2 expression is increased in microglia/macrophages after ischemic stroke

•CMPK2 knockdown in microglia/macrophages ameliorates ischemic injury in mice

•CMPK2 inhibitor nordihydroguaiaretic acid ameliorates ischemic injury in mice

Summary

Neuroinflammation plays a significant role in ischemic injury, which can be promoted by oxidized mitochondrial DNA (Ox-mtDNA). Cytidine/uridine monophosphate kinase 2 (CMPK2) regulates mtDNA replication, but its role in neuroinflammation and ischemic injury remains unknown. Here, we report that CMPK2 expression is upregulated in monocytes/macrophages and microglia post-stroke in humans and mice, respectively. Microglia/macrophage CMPK2 knockdown using the Cre recombination-dependent adeno-associated virus suppresses the inflammatory responses in the brain, reduces infarcts, and improves neurological outcomes in ischemic CX3CR1Cre/ERT2 mice. Mechanistically, CMPK2 knockdown limits newly synthesized mtDNA and Ox-mtDNA formation and subsequently blocks NLRP3 inflammasome activation in microglia/macrophages. Nordihydroguaiaretic acid (NDGA), as a CMPK2 inhibitor, is discovered to reduce neuroinflammation and ischemic injury in mice and prevent the inflammatory responses in primary human monocytes from ischemic patients. Thus, these findings identify CMPK2 as a promising therapeutic target for ischemic stroke and other brain disorders associated with neuroinflammation.



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