Early glycolytic reprogramming control microglial inflammatory activation

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

Background: Microglial activation-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases. Inflammatory activation of microglial cells is often accompanied by a metabolic switch from oxidative phosphorylation to aerobic glycolysis. However, the roles and molecular mechanisms of glycolysis in microglial activation and neuroinflammation are not yet fully understood. Methods: The anti-inflammatory effects and its underlying mechanisms of glycolytic inhibition in vitro were examined in LPS activated BV-2 microglia or primary microglia cells by ELISA, RT-PCR, Western blot, immunoprecipitation, FACS and NF-κB luciferase reporter assays. The anti-inflammatory and neuroprotective effects of glycolytic inhibitor, 2-DG in vivo were measured in the MPTP-or LPS-induced PD models by immunofluorescence staining, behavior tests and Western blot analysis. Results: We found that LPS rapidly increased glycolysis in microglial cells, and glycolysis inhibitors (2-DG and 3-BPA), siRNA Glut-1 and siRNA HK Ⅱ abolished LPS-induced microglial cell activation. Mechanistic studies demonstrated that glycolysis inhibitors significantly inhibited LPS-induced phosphorylation of mTOR, IKKβ and IκB, degradation of IκB, nuclear translocation of p65 and NF-κB transcriptional activity. In addition, 2-DG significantly inhibited LPS-induced acetylation of p65/RelA on lysine 310, which is mediated by NAD + -dependent SIRT1 and is critical for NF-kB activation. A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect. An in vivo study demonstrated that 2-DG significantly ameliorated neuroinflammation and subsequent DA neuronal cell injuries in an LPS-induced Parkinson’s disease (PD) model. Furthermore, 2-DG also reduced TH-positive cell loss and microglial activation in the MPTP-induced PD model. Conclusions: Collectively, our results suggest that glycolysis is actively involved in microglial activation and, hence, that inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.

Related topics