Cited by 641Sepsis Diagnosis and TreatmentInflammation biomarkers and pathwaysImmune Response and Inflammation

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Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

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Cheng, Shih-Chin, Scicluna, Brendon P, Arts, Rob J W, Gresnigt, Mark S, Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J, Kox, Matthijs, Manjeri, Ganesh R, Wagenaars, Jori A L, Cremer, Olaf L, Leentjens, Jenneke, van der Meer, Anne J, van de Veerdonk, Frank L, Bonten, Marc J, Schultz, Marcus J, Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, Netea, Mihai G·2016·Nature Immunology

DOI 10.1038/ni.3398

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Abstract

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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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: Cheng, Shih-Chin
Scicluna, Brendon P
Arts, Rob J W
Gresnigt, Mark S
Giamarellos-Bourboulis, Evangelos J
Kox, Matthijs
Cremer, Olaf L
Leentjens, Jenneke
Bonten, Marc J
Schultz, Marcus J
Willems, Peter H G M
Pickkers, Peter
Joosten, Leo A B
Netea, Mihai G
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2016-03-07
Volume: 17
Issue: 4
Pages: 406-413
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.3398
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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Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

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