Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells
Open accessAbstract
TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte–derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte–derived DCs.
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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 [39]
NO-mediated mitochondrial inhibition in dendritic cells switches metabolism from oxidative to glycolytic, similar to the Warburg effect in hypoxic cancer cells.
“For example NO-mediated mitochondrial inhibition in dendritic cells leads to a switch from oxidative to glycolic metabolism similar to the Warburg effect that is observed in hypoxic cancer cells [216].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [216]
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- Authors
- Everts, B., Amiel, E., van der Windt, G. J. W., Freitas, T. C., Chott, R., Yarasheski, K. E., Pearce, E. L., & Pearce, E. J.
- Affiliations
- Trudeau Institute (US)
- Washington University School of Medicine, St Louis, MO; and
- Washington University in St. Louis (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-08-16
- Volume
- 120
- Issue
- 7
- Pages
- 1422-1431
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3423780
- OpenAlex
- W2042849313
- Cited by
- 532
- References
- 42
- Citations by year
- 2026: 26 · 2025: 19 · 2024: 30 · 2023: 37 · 2022: 37 · 2021: 68 · 2020: 64 · 2019: 55 · 2018: 52 · 2017: 39 · 2016: 38 · 2015: 28 · 2014: 25 · 2013: 13 · 2012: 1
- FWCI
- 7.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (5p60dk020579-35, 5p41rr000954-34)
- National Cancer Institute (R01CA164062)
- National Institute of Allergy and Infectious Diseases (R01AI091965, T32AI049823, R01AI053825, AI53825)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 056341, DK‐020579, P60-DK-020579, P30DK056341, P30DK020579)
- National Center for Research Resources (P41-RR000954, RR-000954)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- dendritic cells, glycolysis, oxidative phosphorylation, nitric oxide, inducible nitric oxide synthase, Toll-like receptor signaling, dendritic cell survival, mitochondrial dysfunction, glucose restriction, ATP levels, monocyte-derived dendritic cells, inflammation, cellular metabolism
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Survival, Dendritic Cells, Glycolysis, Inflammation, Lipopolysaccharides, Mice, Inbred C57BL, Mitochondria, Monocytes, Nitric Oxide, Time Factors, Cell Death, Models, Immunological, Cell Respiration, Toll-Like Receptors, Mice, Nitric Oxide Synthase Type II
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