The Sedoheptulose Kinase CARKL Directs Macrophage Polarization through Control of Glucose Metabolism
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Immune cells are somewhat unique in that activation responses can alter quantitative phenotypes upwards of 100,000-fold. To date little is known about the metabolic adaptations necessary to mount such dramatic phenotypic shifts. Screening for novel regulators of macrophage activation, we found nonprotein kinases of glucose metabolism among the most enriched classes of candidate immune modulators. We find that one of these, the carbohydrate kinase-like protein CARKL, is rapidly downregulated in vitro and in vivo upon LPS stimulation in both mice and humans. Interestingly, CARKL catalyzes an orphan reaction in the pentose phosphate pathway, refocusing cellular metabolism to a high-redox state upon physiological or artificial downregulation. We find that CARKL-dependent metabolic reprogramming is required for proper M1- and M2-like macrophage polarization and uncover a rate-limiting requirement for appropriate glucose flux in macrophage polarization.
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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 [43]
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- Authors
- Haschemi, A., Kosma, P., Gille, L., Evans, C. R., Burant, C. F., Starkl, P., Knapp, B., Haas, R., Schmid, J. A., Jandl, C., Amir, S., Lubec, G., Park, J., Esterbauer, H., Bilban, M., Brizuela, L., Pospisilik, J. A., Otterbein, L. E., & Wagner, O.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- BOKU University (AT)
- University of Veterinary Medicine Vienna (AT)
- University of Michigan (US)
- Medical University of Vienna (AT)
- Harvard University (US)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Corresponding author
- Haschemi, Arvand
- Pospisilik, J. Andrew
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 15
- Issue
- 6
- Pages
- 813-826
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3370649
- OpenAlex
- W2047563937
- Cited by
- 635
- References
- 53
- Citations by year
- 2026: 30 · 2025: 35 · 2024: 68 · 2023: 56 · 2022: 41 · 2021: 60 · 2020: 57 · 2019: 50 · 2018: 48 · 2017: 61 · 2016: 35 · 2015: 41 · 2014: 24 · 2013: 14 · 2012: 3
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Bundesministerium für Wissenschaft und Forschung
- National Institute of General Medical Sciences (R01GM088666)
- National Institute of Diabetes and Digestive and Kidney Diseases (K25DK092558, DK089503, P30DK089503)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- macrophage polarization, glucose metabolism, pentose phosphate pathway, metabolic reprogramming, M1/M2 macrophages, lipopolysaccharide stimulation, redox state, immune cell metabolism
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Double-Blind Method, Energy Metabolism, Glucose, Humans, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Models, Molecular, Phenotype, Receptors, Immunologic, Transcription Factors, Tumor Necrosis Factor-alpha, Down-Regulation, Interleukin-6, Gene Expression Regulation, Enzymologic, Cell Polarity, Protein Structure, Tertiary, Phosphotransferases (Alcohol Group Acceptor), Endotoxemia, Carbohydrate Metabolism, Mice
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