| First Author | Guan X | Year | 2024 |
| Journal | Cell Rep Med | Volume | 5 |
| Issue | 5 | Pages | 101522 |
| PubMed ID | 38701781 | Mgi Jnum | J:357566 |
| Mgi Id | MGI:7657959 | Doi | 10.1016/j.xcrm.2024.101522 |
| Citation | Guan X, et al. (2024) Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke. Cell Rep Med 5(5):101522 |
| abstractText | 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 CX(3)CR1(Cre/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. |
