The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-κB pathway

Han, Chaojun; Zheng, Jiyue; Sun, Lin; Yang, Hui‐Jun; Cao, Zhongqiang; Zhang, Xiaohu; Zheng, Longtai; Zhen, Xuechu

doi:10.1038/s41401-019-0225-9

Cited by 49 publications

(32 citation statements)

References 64 publications

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“…mTOR promotes NF-κB transcriptional activity by directly interacting with IKK, and the inhibition of mTOR by rapamycin reduces proin ammatory gene expression by blocking NF-κB activation in microglial cells [37]. Our previous study also demonstrated that rapamycin signi cantly suppressed IKKβ phosphorylation in LPS-activated BV-2 microglial cells [27]. In the present study, we found that inhibition of glycolysis suppressed LPS-induced mTOR phosphorylation.…”

Section: Discussionsupporting

confidence: 71%

“…Given that TAK1 was not involved in the anti-in ammatory effects of the glycolytic inhibitors in microglial cells, another signaling molecule may be upstream of IKKβ and p65. There are several lines of evidence showing that mTOR, a downstream molecule of AMPK, is involved in the activation of NF-κB signaling pathways [34][35][36]. mTOR promotes NF-κB transcriptional activity by directly interacting with IKK, and the inhibition of mTOR by rapamycin reduces proin ammatory gene expression by blocking NF-κB activation in microglial cells [37].…”

Section: Discussionmentioning

confidence: 99%

“…Since only one of two downstream molecules of TAK1 was inhibited by the glycolytic inhibitors, we speculated that another upstream regulator of IKKβ may be involved in the anti-in ammatory activity of glycolytic inhibitors. AMPK/mTOR has been reported to positively regulate IKKβ activation [26,27].…”

Section: Glycolytic Inhibitors Suppress Lps-induced Activation Of Nf-mentioning

confidence: 99%

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Early glycolytic reprogramming control microglial inflammatory activation

Cheng¹,

Zhang²,

Ke³

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Glycolytic Inhibitors Suppress Lps-induced Activation Of Nf-mentioning

confidence: 99%

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Early glycolytic reprogramming control microglial inflammatory activation

Cheng¹,

Zhang²,

Ke³

et al. 2020

Preprint

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“…Support for potential mutation-specific effects on GAM recruitment comes from two studies: First, murine high-grade gliomas harboring a mutant IDH1 allele exhibited reduced macrophage and microglia infiltration, which correlated with lower levels of chemokine expression (e.g., CCL2, CXCL2) [Amankulor et al, 2017]. Moreover, the IDH1/2-mediated accumulation of the oncometabolite 2-hydroxyglutarate reduced the expression of proinflammatory chemokines [Han et al, 2019]. Second, differences in microglia recruitment were observed in mice genetically engineered to develop low-grade gliomas with distinct patient-derived germline NF1 gene mutations and cooperating genetic alterations (e.g., heterozygous Pten loss) through the elaboration of chemokines [Guo et al, 2019].…”

Section: Glioma Cells Attract/recruit Gammentioning

confidence: 99%

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology

Gutmann

Kettenmann

2019

Neuron

206

247

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One of the most common brain tumors in children and adults is the glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy and radiation. Over the past decade, it is now appreciated that these tumors are comprised of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these non-cancerous cell types, monocytes (microglia and macrophages) predominate. In this review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy.

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“…In contrast, D-2HG suppresses anti-tumor T cell activity by interfering with TCR signaling and polyamine biosynthesis in a mouse glioma model [71]. Immune inhibitory functions were also found in dendritic cells (DCs) [72] and microglia, where D-2HG inhibits activation by AMP-activated protein kinase (AMPK)-mediated downregulation of mTOR and downstream nuclear factor κB (NF-κB)-induced inflammatory responses [73]. Interestingly, IDH mutations are generally associated with longer patient survival and better response to therapy [74], likely due to reduced myeloid cell infiltration and improved vasculature [75,76].…”

Section: D-2hg Suppresses the Immune Response And Reduces Immune Cellmentioning

confidence: 99%

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

Goede

Driessen

Bossche

2020

Biology

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Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

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The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-κB pathway

Cited by 49 publications

References 64 publications

Early glycolytic reprogramming control microglial inflammatory activation

Early glycolytic reprogramming control microglial inflammatory activation

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

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