Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

Kornberg, Michael D.; Bhargava, Pavan; Kim, Paul M.; Putluri, Vasanta; Snowman, Adele M.; Putluri, Nagireddy; Calabresi, Peter A.; Snyder, Solomon H.

doi:10.1126/science.aan4665

Cited by 528 publications

(519 citation statements)

References 37 publications

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“…Pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2) converts the inactive PDH to its active form. Finally, dimethyl fumarate, a derivative of the Krebs cycle intermediate fumarate that inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and therefore inhibits both branches of glycolysis, altered the differentiation and function of Th1 and Th17 cells, attenuating disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis [46], stressing again the potentials of glucose metabolic inhibitors to target pathogenic autoreactive T cells. This may be due at least partly to the direct control of energy production by the transcription factor-inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) at the PDH metabolism bifurcation level [44].…”

Section: Glycolysismentioning

confidence: 99%

Immune cell metabolism in autoimmunity

Teng

Cornaby

et al. 2019

Clinical and Experimental Immunology

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Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases. mental Immunology 2019, 197: 141-142. T cell metabolism in chronic viral infection. Clinical and Experimental Immunology 2019, 197: 143-152. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clinical and Experimental Immunology 2019, 197: 153-160. Sensing between reactions -how the metabolic microenvironment shapes immunity. Clinical and Experimental Immunology 2019, 197: 161-169. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIES Translating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response. Clinical and Experi

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Section: Glycolysismentioning

confidence: 99%

Immune cell metabolism in autoimmunity

Teng

Cornaby

et al. 2019

Clinical and Experimental Immunology

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“…31 With regard to the Treg cells, fatty acid oxidation is shown to promote Treg differentiation, and furthermore genes involved in fatty acid oxidation, as represented by Cpt1a, are reportedly increased. 33 The postulated mechanism was that nuclear factor (erythroidderived 2)-related factor 2 enhances the anti-oxidant effects. 31 Novel mode of action of dimethyl fumarate regulating immune metabolism A novel mode of action regarding dimethyl fumarate (DMF) was recently reported.…”

Section: Metabolic Reprogramming In Pro-inflammatory Immune Subsetsmentioning

confidence: 99%

“…33 GAPDH is a critical enzyme mediating the intracellular glycolytic pathway, and DMF was shown to succinate GAPDH, leading to decreased GAPDH activity in mice. 33 GAPDH is a critical enzyme mediating the intracellular glycolytic pathway, and DMF was shown to succinate GAPDH, leading to decreased GAPDH activity in mice.…”

Section: Metabolic Reprogramming In Pro-inflammatory Immune Subsetsmentioning

confidence: 99%

“…33 As for the effect of DMF on CD4 + T cells, DMF treatment inhibits differentiation of Th1 and Th17 cells. Similarly, blockade of glycolytic flux was also noted in lipopolysaccharides-stimulated mouse peritoneal macrophages (mPMs), without affecting OXPHOS.…”

Section: Metabolic Reprogramming In Pro-inflammatory Immune Subsetsmentioning

confidence: 99%

“…Similarly, blockade of glycolytic flux was also noted in lipopolysaccharides-stimulated mouse peritoneal macrophages (mPMs), without affecting OXPHOS. 33 Overall, the novel mode of DMF action revealed by inhibiting the glycolytic pathway indicates intervention of metabolic pathways in immune cells as a novel therapeutic approach to autoimmune diseases. 33 As for the effect of DMF on CD4 + T cells, DMF treatment inhibits differentiation of Th1 and Th17 cells.…”

Section: Metabolic Reprogramming In Pro-inflammatory Immune Subsetsmentioning

confidence: 99%

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Role of diet, gut microbiota, and metabolism in multiple sclerosis and neuromyelitis optica

Okuno

Kinoshita

Ishikura

et al. 2019

Clinical & Exp Neuroim

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The prevalence of multiple sclerosis (MS) has been increasing over the past two decades, especially in certain areas, such as the Mediterranean regions and Japan. This increase might be attributed to an altered microbiota and metabolic status in accordance with a change in food habits. Studies on an animal model of MS have led to the hypotheses suggesting the pathogenic role of altered gut microbiota and cellular metabolism of immune cells in MS. Recent studies showed that patients with MS have a distinct gut microbiota composition compared with healthy controls. Furthermore, accumulating evidence highlights the critical role of dysregulated immune cell metabolism in autoimmunity. Regarding neuromyelitis optica (NMO), its microbiome has been reported to have distinct features in comparison with healthy controls and MS. Interestingly, molecular mimicry between aquaporin 4 and components of Clostridium perfringens, the second most significantly enriched taxon in NMO, is suggested. CD4 + T cells recognizing the dominant aquaporin 4 T-cell epitope show the T helper 17 cell phenotype, and show cross-reactivity to a homologous peptide sequence in NMO patients. These results raise the possibility that commensal bacteria in NMO patients might be involved in aquaporin 4 autoantibody production. In the present review, we introduce the current advances in the research of food habit and microbiota in MS and NMO in terms of intestinal immunity and immune-metabolic interactions. In addition, we discuss the potential perspective of diet therapy and probiotics in terms of prophylactic or therapeutic treatment options for MS and NMO. Multiple sclerosis and environmental factorsMultiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, and is characterized by inflammatory demyelination and secondary neurodegeneration. 1 MS is a leading cause of disability in young adults, affecting an estimated 2.5 million people worldwide. Myelin-reactive CD4 + cells are thought to play the main pathogenic role in relapsing-remitting MS (RRMS). 1 Although the etiology of MS is not fully understood, genetic studies have shown that human leukocyte antigen (HLA) alleles, including DRB1*1501, are related to susceptibility to MS. 2,3 These major histocompatibility complex class II genes are involved in antigen presentation to CD4 + T cells, which leads to autoimmunity in the central nervous system. Recently, genome-wide association studies have shown that several other genes involved in the immune response, including those related to major histocompatibility complex class I, are also related genes of MS, supporting the notion that this disease is fundamentally an immune-mediated disease. 4 Recent research has shown that environmental factors play important roles in the pathogenesis of MS in addition to genetic factors. One of the most important environmental factors is geographical location, with a higher disease incidence being noted at higher latitudes. 5 This north-south gradient has been hypothesized to be attributabl...

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Selective activation of cellular stress response pathways by fumaric acid esters

Erler,

Krafczyk,

Steinbrenner

et al. 2024

FEBS Open Bio

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The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling.

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Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

Cited by 528 publications

References 37 publications

Immune cell metabolism in autoimmunity

Immune cell metabolism in autoimmunity

Role of diet, gut microbiota, and metabolism in multiple sclerosis and neuromyelitis optica

Selective activation of cellular stress response pathways by fumaric acid esters

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