Research output: Contribution to journal › Article › Academic › peer-review
Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. / Cheng, Shih-Chin; Scicluna, Brendon P.; Arts, Rob J. W. et al.
In: Nature immunology, Vol. 17, No. 4, 2016, p. 406-413.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
AU - Cheng, Shih-Chin
AU - Scicluna, Brendon P.
AU - Arts, Rob J. W.
AU - Gresnigt, Mark S.
AU - Lachmandas, Ekta
AU - Giamarellos-Bourboulis, Evangelos J.
AU - Kox, Matthijs
AU - Manjeri, Ganesh R.
AU - Wagenaars, Jori A. L.
AU - Cremer, Olaf L.
AU - Leentjens, Jenneke
AU - van der Meer, Anne J.
AU - van de Veerdonk, Frank L.
AU - Bonten, Marc J.
AU - Schultz, Marcus J.
AU - Willems, Peter H. G. M.
AU - Pickkers, Peter
AU - Joosten, Leo A. B.
AU - van der Poll, Tom
AU - Netea, Mihai G.
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - 10.1038/ni.3398
DO - 10.1038/ni.3398
M3 - Article
C2 - 26950237
VL - 17
SP - 406
EP - 413
JO - Nature immunology
JF - Nature immunology
SN - 1529-2908
IS - 4
ER -
ID: 2875274