Early glycolytic reprogramming controls microglial inflammatory activation

Abstract

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 lipopolysaccharide (LPS) activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, immunoprecipitation, flow cytometry, and nuclear factor kappa B (NF-κB) luciferase reporter assays. The anti-inflammatory and neuroprotective effects of glycolytic inhibitor, 2-deoxoy-d-glucose (2-DG) in vivo were measured in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-or LPS-induced Parkinson’s disease (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-bromopyruvic acid (3-BPA)), siRNA glucose transporter type 1 (Glut-1), and siRNA hexokinase (HK) 2 abolished LPS-induced microglial cell activation. Mechanistic studies demonstrated that glycolysis inhibitors significantly inhibited LPS-induced phosphorylation of mechanistic target of rapamycin (mTOR), an inhibitor of nuclear factor-kappa B kinase subunit beta (IKKβ), and NF-kappa-B inhibitor alpha (IκB-α), degradation of IκBα, nuclear translocation of p65 subunit of NF-κB, 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 protein deacetylase sirtuin-1 (SIRT1) and is critical for NF-κB 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. In an LPS-induced PD model, 2-DG significantly ameliorated neuroinflammation and subsequent tyrosine hydroxylase (TH)-positive cell loss. Furthermore, 2-DG also reduced dopaminergic cell death and microglial activation in the MPTP-induced PD model. Conclusions Collectively, our results suggest that glycolysis is actively involved in microglial activation. Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.

Near-infrared light reduces β-amyloid-stimulated microglial toxicity and enhances survival of neurons: mechanisms of light therapy for Alzheimer’s disease

“…In LPS- or Aβ-treated microglia, basal lactate production increased by 36% and 23%; at the same time, there was a decrease in the ratio of oxidative-ATP/glycolytic-ATP by 71% and 52%, respectively (Table 1 ). The obtained results demonstrate the dominance of glycolysis over mitochondrial respiration in activated LPS- or Aβ-treated microglia, which corresponds by the literature data [ 77 ]. Otherwise, light irradiation is able to cancel the effect of Aβ-activated mitochondrial respiration and inhibit glycolysis, which is confirmed by a decrease in basal lactate production to the control values and an increase in mitochondrial ATP production by 61% (Table 1 ).…”

Enhanced glycolysis in granulosa cells promotes the activation of primordial follicles through mTOR signaling

“…Thus, short-term pyruvate deprivation activates mTOR signaling by enhancing glycolysis in granulosa cells and then activates Akt-FOXO3a signaling in oocytes, resulting in mouse and human primordial follicle activation. In contrast, the blockade of glycolysis by 2-DG increased p-AMPK levels and decreased p-mTOR levels in mouse ovaries, resulting in the inhibition of primordial follicle activation, consistent with a previous study showing that glycolysis inhibitors increase p-AMPK levels and decrease p-mTOR levels in mouse glial cells [ 31 ].…”

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

“…For a summary of the metabolic pathways regulated by the circadian clock, please see Figure 2 . Early in the systemic inflammatory response, there is a “glycolytic switch”—seen in initially activated neutrophils ( Sadiku et al, 2021 ), macrophages ( Yu et al, 2020 ), B cells ( Doughty et al, 2006 ), proinflammatory T cells ( Chapman et al, 2020 ), and microglia ( Cheng et al, 2021 ). Therefore, metabolic regulation of inflammation is gaining traction ( Soto-Heredero et al, 2020 ).…”