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

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

doi:10.1038/ni.3398

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

Nat Immunol. 2016 Apr;17(4):406-13. doi: 10.1038/ni.3398. Epub 2016 Mar 7.

Authors

Shih-Chin Cheng¹, Brendon P Scicluna², Rob J W Arts¹, Mark S Gresnigt¹, Ekta Lachmandas¹, Evangelos J Giamarellos-Bourboulis³, Matthijs Kox⁴, Ganesh R Manjeri^{5

6}, Jori A L Wagenaars⁵, Olaf L Cremer⁷, Jenneke Leentjens^{1

4}, Anne J van der Meer², Frank L van de Veerdonk¹, Marc J Bonten^{8

9}, Marcus J Schultz¹⁰, Peter H G M Willems⁵, Peter Pickkers⁴, Leo A B Joosten¹, Tom van der Poll², Mihai G Netea¹

Affiliations

¹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
² Center of Experimental &Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
³ 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.
⁴ Department of Intensive Care and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
⁶ Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
⁷ Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
⁸ Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁰ Department of Intensive Care Medicine Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

PMID: 26950237
DOI: 10.1038/ni.3398

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.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Adult
Animals
Antifungal Agents / therapeutic use
Aspergillosis / drug therapy
Aspergillosis / immunology
Aspergillosis / metabolism
Candidiasis, Invasive / drug therapy
Candidiasis, Invasive / immunology
Candidiasis, Invasive / metabolism
Cytokines / immunology*
Endotoxemia / immunology*
Endotoxemia / metabolism
Energy Metabolism / immunology*
Escherichia coli Infections / immunology
Escherichia coli Infections / metabolism
Female
Glycolysis
Humans
Immune Tolerance / immunology*
Immunity, Innate / immunology*
Immunoblotting
Interferon-gamma / therapeutic use
Lactic Acid / metabolism
Leukocytes / immunology
Leukocytes / metabolism
Lipopolysaccharides / immunology
Macrophages / immunology*
Macrophages / metabolism
Male
Mice
Middle Aged
Monocytes / immunology*
Monocytes / metabolism
NAD / metabolism
Oxidative Phosphorylation
Oxygen Consumption
Prospective Studies
Sepsis / drug therapy
Sepsis / immunology*
Sepsis / metabolism
Transcriptome
Young Adult

Substances

Antifungal Agents
Cytokines
Lipopolysaccharides
NAD
Lactic Acid
Interferon-gamma
Adenosine Triphosphate