Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction,Journal of Advanced Research

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Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-13 , DOI: 10.1016/j.jare.2024.08.016
Yin Li ₁ , Hang Zhou ₁ , Xuchao He ₁ , Lingji Jin ₁ , Yuhan Zhu ₁ , Libin Hu ₁ , Majing Feng ₂ , Jun Zhu ₂ , Liang Wang ₂ , Yonghe Zheng ₁ , Shiwei Li ₂ , Zhiyuan Yan ₂ , Peili Cen ₃ , Junwen Hu ₁ , Zihang Chen ₁ , Xiaobo Yu ₁ , Xiongjie Fu ₁ , Chaoran Xu ₁ , Shenglong Cao ₁ , Yang Cao ₄ , Gao Chen ₁ , Lin Wang ₁

Affiliation

Introduction

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.

Objectives

This study investigated microglial glycolysis and its mechanistic effects on microglial inflammation after ICH.

Methods

We explored the status of glucose metabolism in the ipsilateral region and in fluorescence-activated-cell-sorting-isolated (FACS-isolated) microglia via 2-deoxy-[¹⁸F]fluoro-D-glucose positron emission tomography (FDG-PET) analyses and gamma emission, respectively. Energy-related targeted metabolomics, along with ¹³C-glucose isotope tracing, was utilised to analyse glycolytic products in microglia. Mitochondrial membrane potential and mitochondrial reactive oxygen species (MitoROS) accumulation was assessed by flow cytometry. Behavioural, western blotting, gene regulation, and enzymatic activity analyses were conducted with a focus on microglia.

Results

Neurological dysfunction was strongly correlated with decreased FDG-PET signals in the perihaematomal region, where microglial uptake of FDG was reduced. The decreased quantity of glucose-6-phosphate (G-6-P) in microglia was attributed to the downregulation of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Enhanced inflammatory responses were driven by HK2 suppression via decreased mitochondrial membrane potential, which could be rescued by MitoROS scavengers. HK inhibitors aggravated neurological injury by suppressing FDG uptake and enhancing microglial inflammation in ICH mice.

Conclusion

These findings indicate an unexpected metabolic status in pro-inflammatory microglia after ICH, consisting of glycolysis impairment caused by the downregulation of GLUT1 and HK2. Additionally, HK2 suppression promotes inflammatory responses by disrupting mitochondrial function, providing insight into the mechanisms by which inflammation may be facilitated after ICH and indicating that metabolic enzymes as potential targets for ICH treatment.

中文翻译：

小胶质细胞糖酵解受损通过 HK2 依赖性线粒体功能障碍促进脑出血后的炎症反应

介绍

脑出血（ICH）是一种导致严重神经功能缺损的毁灭性疾病。小胶质细胞是大脑的第一道防线，在 ICH 后的神经恢复中起着至关重要的作用，其活动主要由葡萄糖代谢驱动。然而，关于小胶质细胞中葡萄糖代谢的状态及其与 ICH 后炎症反应的相互作用知之甚少。

目标

本研究调查了小胶质细胞糖酵解及其对 ICH 后小胶质细胞炎症的机制影响。

方法

我们分别通过 2-脱氧-[¹⁸F]fluoro-D-葡萄糖正电子发射断层扫描（FDG-PET）分析和 γ 发射探讨了同侧区域和荧光激活细胞分选分离（FACS 分离）小胶质细胞的葡萄糖代谢状况。利用能量相关的靶向代谢组学以及 ¹³C-葡萄糖同位素示踪来分析小胶质细胞中的糖酵解产物。通过流式细胞术评估线粒体膜电位和线粒体活性氧（MitoROS）积累。以小胶质细胞为重点进行行为、蛋白质印迹、基因调控和酶活性分析。

结果

神经功能障碍与血肿周围区域的 FDG-PET 信号减少密切相关，其中小胶质细胞对 FDG 的摄取减少。小胶质细胞中葡萄糖-6-磷酸（G-6-P）数量的减少归因于葡萄糖转运蛋白 1 （GLUT1）和己糖激酶 2 （HK2）的下调。通过降低线粒体膜电位抑制 HK2 驱动炎症反应增强，这可以通过 MitoROS 清除剂来挽救。HK 抑制剂通过抑制 ICH 小鼠的 FDG 摄取和增强小胶质细胞炎症来加重神经损伤。