[HTML][HTML] Glucose transporter 1 critically controls microglial activation through facilitating glycolysis
Molecular neurodegeneration, 2019•Springer
Background Uncontrolled microglial activation contributes to the pathogenesis of various
neurodegenerative diseases. Previous studies have shown that proinflammatory microglia
are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed
to understand how glucose uptake is facilitated in active microglia and whether microglial
activation can be controlled by restricting glucose uptake. Methods Primary murine brain
microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with …
neurodegenerative diseases. Previous studies have shown that proinflammatory microglia
are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed
to understand how glucose uptake is facilitated in active microglia and whether microglial
activation can be controlled by restricting glucose uptake. Methods Primary murine brain
microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with …
Background
Uncontrolled microglial activation contributes to the pathogenesis of various neurodegenerative diseases. Previous studies have shown that proinflammatory microglia are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed to understand how glucose uptake is facilitated in active microglia and whether microglial activation can be controlled by restricting glucose uptake.
Methods
Primary murine brain microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with LPS (100 ng/ml) + IFNγ (100 ng/ml) or IL-4 (20 ng/ml) for 24 h. The expression of glucose transporters (GLUTs) was examined by PCR and Western blot. Glucose uptake by microglia was inhibited using the GLUT1-specific inhibitor STF31. The metabolic profiles were tested using the Glycolysis Stress Test and Mito Stress Test Kits using the Seahorse XFe96 Analyser. Inflammatory gene expression was examined by real-time RT-PCR and protein secretion by cytokine beads array. The effect of STF31 on microglial activation and neurodegeneraion was further tested in a mouse model of light-induced retinal degeneration.
Results
The mRNA and protein of GLUT1, 3, 4, 5, 6, 8, 9, 10, 12, and 13 were detected in microglia. The expression level of GLUT1 was the highest among all GLUTs detected. LPS + IFNγ treatment further increased GLUT1 expression. STF31 dose-dependently reduced glucose uptake and suppressed Extracellular Acidification Rate (ECAR) in naïve, M(LPS + IFNγ) and M(IL-4) microglia. The treatment also prevented the upregulation of inflammatory cytokines including TNFα, IL-1β, IL-6, and CCL2 in M(LPS + IFNγ) microglia. Interestingly, the Oxygen Consumption Rates (OCR) was increased in M(LPS + IFNγ) microglia but reduced in M(IL-4) microglia by STF31 treatment. Intraperitoneal injection of STF31 reduced light-induced microglial activation and retinal degeneration.
Conclusion
Glucose uptake in microglia is facilitated predominately by GLUT1, particularly under inflammatory conditions. Targeting GLUT1 could be an effective approach to control neuroinflammation.
Springer