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

Sepsis is poorly understood, largely untreatable and frequently fatal. Netea and colleagues assess both mouse sepsis and human sepsis to demonstrate that its late phase is characterized by immunoparalysis and broad metabolic alterations in cells of the immune system. The acute phase of sepsis is cha...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nature immunology 2016-04, Vol.17 (4), p.406-413
Hauptverfasser: 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
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Sepsis is poorly understood, largely untreatable and frequently fatal. Netea and colleagues assess both mouse sepsis and human sepsis to demonstrate that its late phase is characterized by immunoparalysis and broad metabolic alterations in cells of the immune system. 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.
ISSN:1529-2908
1529-2916
DOI:10.1038/ni.3398