1. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis.
- Author
-
Cheng SC, Scicluna BP, Arts RJ, Gresnigt MS, Lachmandas E, Giamarellos-Bourboulis EJ, Kox M, Manjeri GR, Wagenaars JA, Cremer OL, Leentjens J, van der Meer AJ, van de Veerdonk FL, Bonten MJ, Schultz MJ, Willems PH, Pickkers P, Joosten LA, van der Poll T, and Netea MG
- Subjects
- Adenosine Triphosphate metabolism, Adult, Animals, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillosis immunology, Aspergillosis metabolism, Candidiasis, Invasive drug therapy, Candidiasis, Invasive immunology, Candidiasis, Invasive metabolism, Endotoxemia metabolism, Escherichia coli Infections immunology, Escherichia coli Infections metabolism, Female, Glycolysis, Humans, Immunoblotting, Interferon-gamma therapeutic use, Lactic Acid metabolism, Leukocytes immunology, Leukocytes metabolism, Lipopolysaccharides immunology, Macrophages metabolism, Male, Mice, Middle Aged, Monocytes metabolism, NAD metabolism, Oxidative Phosphorylation, Oxygen Consumption, Prospective Studies, Sepsis drug therapy, Sepsis metabolism, Transcriptome, Young Adult, Cytokines immunology, Endotoxemia immunology, Energy Metabolism immunology, Immune Tolerance immunology, Immunity, Innate immunology, Macrophages immunology, Monocytes immunology, Sepsis immunology
- 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.
- Published
- 2016
- Full Text
- View/download PDF