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Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
Open accessAbstract
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.
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“Metabolic inflexibility drives sepsis-related innate immunoparalysis as the metabolism through glycolysis, β-oxidation, and OXPHOS pathways in leukocytes is downregulated, resulting in their inability to mount any response whatsoever (171).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [171]
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The immunopathology of sepsis and potential therapeutic targets
van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P., & Netea, M. G. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.36 · Cited by 1,957
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α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
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Macrophage Immunometabolism: Where Are We (Going)?
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Metadata
- Authors
- Cheng, S.-C., Scicluna, B. P., Arts, R. J. W., Gresnigt, M. S., Lachmandas, E., Giamarellos-Bourboulis, E. J., Kox, M., Manjeri, G. R., Wagenaars, J. A. L., Cremer, O. L., Leentjens, J., van der Meer, A. J., van de Veerdonk, F. L., Bonten, M. J., Schultz, M. J., Willems, P. H. G. M., Pickkers, P., Joosten, L. A. B., van der Poll, T., & Netea, M. G.
- Affiliations
- Radboud University Medical Center (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Radboud University Nijmegen (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- University Medical Center Utrecht (NL)
- Corresponding author
- Netea, Mihai G
- ORCID
- Venue
- Nature Immunology
- Published
- 2016-03-07
- Volume
- 17
- Issue
- 4
- Pages
- 406-413
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2296531152
- Cited by
- 637
- References
- 62
- Citations by year
- 2026: 63 · 2025: 66 · 2024: 65 · 2023: 61 · 2022: 59 · 2021: 73 · 2020: 83 · 2019: 54 · 2018: 59 · 2017: 39 · 2016: 13
- FWCI
- 51.49
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Center for Translational Molecular Medicine (04I-201)
- FP7 Ideas: European Research Council (310372)
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- sepsis, immunoparalysis, leukocyte metabolism, immunometabolism, oxidative phosphorylation, aerobic glycolysis, metformin, systemic fungal infection, lipopolysaccharide tolerance, interferon-gamma, cytokine production, metabolite profiling
- MeSH terms
- Adenosine Triphosphate, Adult, Animals, Antifungal Agents, Aspergillosis, Energy Metabolism, Escherichia coli Infections, Female, Glycolysis, Humans, Immune Tolerance, Immunity, Innate, Interferon-gamma, Leukocytes, Lipopolysaccharides, Macrophages, Male, Middle Aged, Monocytes, NAD, Oxidative Phosphorylation, Oxygen Consumption, Prospective Studies, Immunoblotting, Cytokines, Sepsis, Lactic Acid, Endotoxemia, Mice, Young Adult, Candidiasis, Invasive, Transcriptome
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