Department of Rehabilitation Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.
Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Sichuan, China.
Neurobiol Dis. 2023 Sep;185:106253. doi: 10.1016/j.nbd.2023.106253. Epub 2023 Aug 2.
N6-methyladenosine (m6A) plays a crucial role in ischemic stroke, whereas the role of methyltransferase-like 14 (METTL14) in ischemic stroke remains unknown. A model of middle cerebral artery occlusion (MCAO) in rats and oxygen-glucose deprivation/reperfusion (OGD/R) model in HAPI cells were used to simulate ischemic stroke in vivo and in vitro. We found that METTL14 level was upregulated in microglia/macrophage after MCAO and OGD/R. METTL14 enhanced the expression of KAT3B by promoting the m6A modification of KAT3B mRNA. STING has been identified as a target for KAT3B and KAT3B increased STING expression by enhancing H3K27ac in the STING promoter. METTL14 promoted M1 polarization and NLRP3 inflammasome/pyroptosis axis by the KAT3B-STING signaling after OGD/R. METTL14 depletion relieved brain injury by inhibiting M1-like microglia/macrophage polarization and NLRP3 inflammasome/pyroptosis axis in MCAO rats. These findings indicate that METTL14 depletion relieves MCAO-induced brain injury, probably via switching microglia/macrophage from M1 towards M2 and restraining NLRP3 inflammasome/pyroptosis axis in microglia/macrophage.
N6-甲基腺苷（m6A）在缺血性卒中中发挥关键作用，而甲基转移酶样 14（METTL14）在缺血性卒中中的作用尚不清楚。我们使用大鼠大脑中动脉闭塞（MCAO）模型和 HAPI 细胞的氧葡萄糖剥夺/再灌注（OGD/R）模型，在体内和体外模拟缺血性卒中。我们发现，METTL14 在 MCAO 和 OGD/R 后小胶质细胞/巨噬细胞中上调。METTL14 通过促进 KAT3B mRNA 的 m6A 修饰来增强 KAT3B 的表达。STING 已被确定为 KAT3B 的靶标，并且 KAT3B 通过增强 STING 启动子中的 H3K27ac 来增加 STING 的表达。METTL14 通过 OGD/R 后的 KAT3B-STING 信号促进 M1 极化和 NLRP3 炎性体/焦亡轴。METTL14 耗竭通过抑制 MCAO 大鼠中 M1 样小胶质细胞/巨噬细胞极化和 NLRP3 炎性体/焦亡轴，减轻脑损伤。这些发现表明，METTL14 耗竭通过将小胶质细胞/巨噬细胞从 M1 向 M2 转变并抑制小胶质细胞/巨噬细胞中的 NLRP3 炎性体/焦亡轴，从而减轻 MCAO 诱导的脑损伤。
