Cited by 1,064Immune Response and InflammationImmunotherapy and Immune ResponsesCancer, Hypoxia, and Metabolism

TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation

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Everts, Bart, Amiel, Eyal, Huang, Stanley Ching-Cheng, Smith, Amber M, Chang, Chih-Hao, Lam, Wing Y, Redmann, Veronika, Freitas, Tori C +6 more·2014·Nature Immunology

Abstract

The ligation of Toll-like receptors (TLRs) leads to rapid activation of dendritic cells (DCs). However, the metabolic requirements that support this process remain poorly defined. We found that DC glycolytic flux increased within minutes of exposure to TLR agonists and that this served an essential role in supporting the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi required for the production and secretion of proteins that are integral to DC activation. Signaling via the kinases TBK1, IKKɛ and Akt was essential for the TLR-induced increase in glycolysis by promoting the association of the glycolytic enzyme HK-II with mitochondria. In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs.

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Crossref · 10.1038/ni.2833

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  • The increased degradation of key enzymes SUCLA2, ALDH2, and ACO2 is consistent with a reported shift in LPS-stimulated DCs from oxidative phosphorylation and oxygen consumption to glycolysis, glucose consumption, and lactate production.

    “The increased degradation of key enzymes, such as SUCLA2, ALDH2 and ACO2, is consistent with a reported shift in LPS-stimulated DCs from oxidative phosphorylation and oxygen consumption to glycolysis, glucose consumption and lactate production (39–42).”
  • Metabolic state is directly manipulated by cytokine and pattern-recognition receptors, and elevated glycolytic activity has been linked to immune cell activation.

    “Metabolic state is directly manipulated by cytokine and pattern-recognition receptors, and elevated glycolytic activity has been tied to immune cell activation (Everts et al., 2014; O’Neill and Pearce, 2016).”

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Authors
Everts, B., Amiel, E., Huang, S. C.-C., Smith, A. M., Chang, C.-H., Lam, W. Y., Redmann, V., Freitas, T. C., Blagih, J., van der Windt, G. J. W., Artyomov, M. N., Jones, R. G., Pearce, E. L., & Pearce, E. J.
Affiliations
  • Washington University in St. Louis (US)
  • University of Vermont (US)
  • Trudeau Institute (US)
  • McGill University (CA)
Corresponding author
  • Pearce, Erika L
  • Pearce, Edward J
Venue
Nature Immunology
Published
2014-02-23
Volume
15
Issue
4
Pages
323-332
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
OpenAlex
W2054828149
Cited by
1,064
References
48
Citations by year
2026: 75 · 2025: 84 · 2024: 89 · 2023: 99 · 2022: 93 · 2021: 119 · 2020: 127 · 2019: 97 · 2018: 81 · 2017: 72 · 2016: 61 · 2015: 44 · 2014: 21
FWCI
30.13
Type
journal article
Language
en
Open access
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • National Institutes of Health
  • National Cancer Institute (CA158823, CA164062, R21CA158823, R01CA164062)
  • National Institute of Allergy and Infectious Diseases (R01AI091965, AI049823, T32AI049823, R01AI053825, AI53825)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
dendritic cell activation, glycolytic reprogramming, Toll-like receptor signaling, TBK1, IKKε, Akt, hexokinase 2, fatty acid synthesis, mitochondrial association, endoplasmic reticulum expansion, Golgi apparatus, dendritic cell metabolism, oxidative phosphorylation
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Dendritic Cells, Fatty Acids, Glycolysis, Hexokinase, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes, Signal Transduction, Protein Serine-Threonine Kinases, Mice, Knockout, RNA, Small Interfering, Proto-Oncogene Proteins c-akt, Toll-Like Receptors, Mice, I-kappa B Kinase

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