Pro-inflammatory Macrophages Sustain Pyruvate Oxidation through Pyruvate Dehydrogenase for the Synthesis of Itaconate and to Enable Cytokine Expression
Open accessAbstract
Upon stimulation with Th1 cytokines or bacterial lipopolysaccharides, resting macrophages shift their phenotype toward a pro-inflammatory state as part of the innate immune response. LPS-activated macrophages undergo profound metabolic changes to adapt to these new physiological requirements. One key step to mediate this metabolic adaptation is the stabilization of HIF1α, which leads to increased glycolysis and lactate release, as well as decreased oxygen consumption. HIF1 abundance can result in the induction of the gene encoding pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) via phosphorylation. Therefore, it has been speculated that pyruvate oxidation through PDH is decreased in pro-inflammatory macrophages. However, to answer this open question, an in-depth analysis of this metabolic branching point was so far lacking. In this work, we applied stable isotope-assisted metabolomics techniques and demonstrate that pyruvate oxidation is maintained in mature pro-inflammatory macrophages. Glucose-derived pyruvate is oxidized via PDH to generate citrate in the mitochondria. Citrate is used for the synthesis of the antimicrobial metabolite itaconate and for lipogenesis. An increased demand for these metabolites decreases citrate oxidation through the tricarboxylic acid cycle, whereas increased glutamine uptake serves to replenish the TCA cycle. Furthermore, we found that the PDH flux is maintained by unchanged PDK1 abundance, despite the presence of HIF1. By pharmacological intervention, we demonstrate that the PDH flux is an important node for M(LPS) macrophage activation. Therefore, PDH represents a metabolic intervention point that might become a research target for translational medicine to treat chronic inflammatory diseases.
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ACLY is phosphorylated in response to IL-2 treatment in CD4+ T-lymphocytes.
“An unbiased mass spectrometry-based study of the nuclear phosphoproteome of resting and IL-2-treated CD4+ T-lymphocytes revealed that ACLY is phosphorylated in response to IL-2 treatment 57.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [57]
ACLY is required to enhance histone acetylation levels and induce expression of cell cycle regulating genes in response to IL-2.
“The authors demonstrate that ACLY is required to enhance histone acetylation levels and induce the expression of cell cycle regulating genes in response to IL-2.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [57]
Pharmacological or genetic ablation of ACLY impairs IL-2-promoted T-cell growth.
“Pharmacological or genetic ablation of ACLY function impaired IL-2-promoted T-cell growth.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [57]
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- Authors
- Meiser, J., Krämer, L., Sapcariu, S. C., Battello, N., Ghelfi, J., D'Herouel, A. F., Skupin, A., & Hiller, K.
- Affiliations
- University of Luxembourg (LU)
- Corresponding author
- Hiller, Karsten
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 291
- Issue
- 8
- Pages
- 3932-3946
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4759172
- OpenAlex
- W2218496732
- Cited by
- 243
- References
- 53
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 30 · 2023: 24 · 2022: 37 · 2021: 25 · 2020: 28 · 2019: 20 · 2018: 24 · 2017: 18 · 2016: 9
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- Funders
- Fonds National de la Recherche Luxembourg (ATTRACT A10/03, AFR-Postdoc-3973022)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- inflammatory macrophages, pyruvate dehydrogenase, pyruvate oxidation, LPS-stimulated macrophages, HIF-1α stabilization, pyruvate dehydrogenase kinase 1, macrophage metabolism, citrate, TCA cycle, glutamine metabolism, lipogenesis, cytokine expression, chronic inflammation
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Cell Line, Gene Expression Regulation, Inflammation, Lipopolysaccharides, Macrophage Activation, Macrophages, Oxidation-Reduction, Pyruvate Dehydrogenase Complex, Succinates, Monokines, Protein Serine-Threonine Kinases, Pyruvic Acid, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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