RESUMEN
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.
Asunto(s)
Accidente Cerebrovascular Isquémico , Microglía , Enfermedades Neuroinflamatorias , Animales , Humanos , Masculino , Ratones , Lesiones Encefálicas/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/genética , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Inflamasomas/metabolismo , Accidente Cerebrovascular Isquémico/patología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/genética , Macrófagos/metabolismo , Macrófagos/patología , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/patología , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Phidianidines A and B are novel marine indole alkaloids with various biological activities. Based on their potential anti-inflammatory properties, a series of phidianidine derivatives were designed, synthesized, and tested for their effects on IL-17A production in PMA/ionomycin-stimulated T-cell-lymphoma EL-4 cells. Compounds 9a and 22c exhibited excellent anti-inflammatory activity and low toxicity, with IC50 values of 7.7 µM and 5.3 µM for IL-17A production in PMA/ionomycin-stimulated EL-4 cells, respectively. Further mechanistic study showed that 9a could decrease the STAT3 phosphorylation at Y705 to inhibit IL-17A production in EL-4 cells, indicating its ability of preventing the differentiation of Th17 cells and their possible function. This research may give an insight for the discovery of marine indole alkaloid derived anti-inflammatory drug leads for the treatment of T cell-mediated diseases.
