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Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
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Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
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Journal Article
Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
2016
Overview
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 14/1
/ 38
/ 38/77
/ Adenosine Triphosphate - metabolism
/ Adult
/ Animals
/ Antifungal Agents - therapeutic use
/ Aspergillosis - drug therapy
/ Candidiasis, Invasive - drug therapy
/ Candidiasis, Invasive - immunology
/ Candidiasis, Invasive - metabolism
/ Complications and side effects
/ Energy Metabolism - immunology
/ Escherichia coli Infections - immunology
/ Escherichia coli Infections - metabolism
/ Female
/ Humans
/ Immune Tolerance - immunology
/ Immunity, Innate - immunology
/ Interferon-gamma - therapeutic use
/ Lipopolysaccharides - immunology
/ Male
/ Mice
/ Sepsis
