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Title: | Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis |
Authors: | 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 Meer, Anne-Jan van der Veerdonk, Frank L. van de Bonten, Marc M.J. Schultz, Marcus J. Willems, Peter H. G. M. Pickkers, Peter Joosten, Leo A.B. Poll, Tom van der Netea, Mihai G. |
Keywords: | Adenosine triphosphate -- Metabolism Antifungal agents -- Research -- Methodology Aspergillosis Cytokines Endotoxins -- Analysis Energy metabolism Escherichia coli infections -- Diagnosis Immunological tolerance Septicemia -- Diagnosis |
Issue Date: | 2016 |
Publisher: | Nature Publishing Group |
Citation: | Cheng, S. C., Scicluna, B. P., Arts, R. J., Gresnigt, M. S., Lachmandas, E., Giamarellos-Bourboulis, E. J., ... & Netea, M. G. (2016). Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nature Immunology, 17(4), 406-413. |
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. |
URI: | https://www.um.edu.mt/library/oar/handle/123456789/96246 |
Appears in Collections: | Scholarly Works - FacHScABS |
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