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Updated: May 12, 2026
A Cell Culture Model for Studying the Role of Neuron-Glia Interactions in Ischemia
Published on: November 14, 2020
Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent
Yin Li1, Hang Zhou1, Xuchao He1
1Department of Neurosurgery & Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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.
Insights
Intracerebral haemorrhage (ICH) impairs microglial glucose metabolism, specifically glycolysis, by downregulating GLUT1 and HK2. This metabolic shift exacerbates inflammation and neurological damage after ICH.
Area of Science:
- Neuroscience
- Metabolic pathways
- Cellular biology
Background:
- Intracerebral haemorrhage (ICH) causes severe neurological deficits.
- Microglia are key in brain recovery post-ICH, relying on glucose metabolism.
- Microglial glucose metabolism and its link to inflammation after ICH remain unclear.
Purpose of the Study:
- Investigate microglial glycolysis status after ICH.
- Elucidate the mechanistic link between microglial glycolysis and inflammation post-ICH.
Main Methods:
- Utilized 2-deoxy-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) and gamma emission for glucose metabolism analysis.
- Employed targeted metabolomics and 13C-glucose isotope tracing to analyze microglial glycolytic products.
- Assessed mitochondrial function (membrane potential, MitoROS) and performed behavioral, western blotting, and gene regulation analyses.
Main Results:
- Reduced FDG-PET signals in the perihaematomal region correlated with neurological dysfunction.
- Microglial glycolysis impairment (decreased G-6-P) was linked to downregulated glucose transporter 1 (GLUT1) and hexokinase 2 (HK2).
- Hexokinase 2 (HK2) suppression worsened inflammation by disrupting mitochondrial function, an effect mitigated by MitoROS scavengers.
Conclusions:
- Pro-inflammatory microglia in ICH exhibit impaired glycolysis due to reduced GLUT1 and HK2.
- HK2 suppression exacerbates ICH-induced inflammation via mitochondrial dysfunction.
- Metabolic enzymes like HK2 represent potential therapeutic targets for treating intracerebral haemorrhage.
