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

Research output: Contribution to journalArticlepeer-review

220 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)406-13
Number of pages8
JournalNature Immunology
Issue number4
Publication statusPublished - 7 Mar 2016


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