Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction

作者：Yin Li, Hang Zhou, Xuchao He, Lingji Jin, Yuhan Zhu, Libin Hu, Ma-Jing Feng, Jun Zhu, Liang Wang, Yonghe Zheng, Shiwei Li, Zhiyuan Yan, Peili Cen, Junwen Hu, Zihang Chen, Xiaobo Yu, Xiongjie Fu, Chaoran Xu, Shenglong Cao, Yang Cao, Gao Chen, Lin Wang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.08.016 · 被引用次数：41 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer

• Decreased glucose metabolism was detected in the perihaematomal region after ICH. • Perihaematomal microglia exhibited impaired glucose metabolism. • The targeted metabolomics, along with 13 C-glucose isotope tracing, confirmed a decline of G-6-P occurred in microglia. • Glucose transporter 1 and HK2 regulated the production of G-6-P after ICH. • HK2 suppression promoted inflammatory responses via affecting mitochondrial function. • HK2 inhibitors enhance inflammatory responses and exacerbated neurological injury after ICH. Intracerebral haemorrhage (ICH) is a devastating disease that leads to severe neurological deficits. Microglia are the first line of defence in the brain and play a crucial role in neurological recovery after ICH, whose activities are primarily driven by glucose metabolism. However, little is known regarding the status of glucose metabolism in microglia and its interactions with inflammatory responses after ICH. This study investigated microglial glycolysis and its mechanistic effects on microglial inflammation after ICH. We explored the status of glucose metabolism in the ipsilateral region and in fluorescence-activated-cell-sorting-isolated (FACS-isolated) microglia via 2-deoxy-[ 18 F]fluoro-D-glucose positron emission tomography (FDG-PET) analyses and gamma emission, respectively. Energy-related targeted metabolomics, along with 13 C-glucose isotope tracing, was utilised to analyse glycolytic products in microglia. Mitochondrial membrane potential and...