Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Open accessAbstract
Dendritic cells (DCs) are key regulators of innate and acquired immunity. The maturation of DCs is directed by signal transduction events downstream of toll-like receptors (TLRs) and other pattern recognition receptors. Here, we demonstrate that, in mouse DCs, TLR agonists stimulate a profound metabolic transition to aerobic glycolysis, similar to the Warburg metabolism displayed by cancer cells. This metabolic switch depends on the phosphatidyl inositol 3′-kinase/Akt pathway, is antagonized by the adenosine monophosphate (AMP)–activated protein kinase (AMPK), and is required for DC maturation. The metabolic switch induced by DC activation is antagonized by the antiinflammatory cytokine interleukin-10. Our data pinpoint TLR-mediated metabolic conversion as essential for DC maturation and function and reveal it as a potential target for intervention in the control of excessive inflammation and inappropriately regulated immune responses.
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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).”
From Dynamic profiling of the protein life cycle in response to pathogens (2015) · cites this paper as [40]
TCR/CD28 stimulation of T cells, surface immunoglobulin stimulation on B cells, and TLR stimulation of macrophages and DCs all promote changes in aerobic glycolysis characteristic of the Warburg effect.
“TCR/CD28 stimulation of T cells (6), the stimulation of surface immunoglobulin on B cells (41), and TLR stimulation of macrophages and dendritic cells (DCs) (42, 43) all promote changes in aerobic glycolysis characteristic of the Warburg effect.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [42]
The increase in IL-10 production may be explained by increased flux of pyruvate into the TCA cycle, because M2 macrophage activity may require mitochondrial oxidative metabolism.
“This could explain the increase in IL-10 production, which in the case of M2 macrophage activity may require mitochondrial oxidative metabolism (Krawczyk et al., 2010).”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Krawczyk et al., 2010
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“Recent data has shown that DCs can do this by switching their core metabolism from oxidative phosphorylation to glycolysis [3].”
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Microglial Function during Glucose Deprivation: Inflammatory and Neuropsychiatric Implications
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Hypoxia and hypoxia-inducible factors in myeloid cell-driven host defense and tissue homeostasis
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Energy metabolism and rheumatic diseases: from cell to organism
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Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target
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mTORC2 deficiency alters the metabolic profile of conventional dendritic cells
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- Authors
- Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis, R. J., Cross, J. R., Jung, E., Thompson, C. B., Jones, R. G., & Pearce, E. J.
- Affiliations
- University of Pennsylvania (US)
- McGill University (CA)
- Trudeau Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Abramson Cancer Center (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-06-10
- Volume
- 115
- Issue
- 23
- Pages
- 4742-4749
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2890190
- OpenAlex
- W2000323986
- Cited by
- 1,246
- References
- 40
- Citations by year
- 2026: 71 · 2025: 84 · 2024: 95 · 2023: 88 · 2022: 112 · 2021: 114 · 2020: 127 · 2019: 105 · 2018: 102 · 2017: 91 · 2016: 65 · 2015: 60 · 2014: 47 · 2013: 42 · 2012: 25
- FWCI
- 11.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Cancer Research Institute
- National Institutes of Health (CA104838)
- Canadian Institutes of Health Research (MOP-93 799)
- National Cancer Institute (P01CA104838, CA104838)
- National Institute of Allergy and Infectious Diseases (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 maturation, Toll-like receptors, aerobic glycolysis, Warburg effect, glycolytic metabolism, PI3K/Akt signaling, AMPK, IL-10, metabolic reprogramming, inflammation control, innate immunity
- MeSH terms
- Animals, Dendritic Cells, Glycolysis, Inflammation, Signal Transduction, Interleukin-10, Mice, Knockout, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Toll-Like Receptors, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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