Τίτλος:
Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2016 Nature America, Inc.
Συγγραφείς:
Cheng, S.-C.
Scicluna, B.P.
Arts, R.J.W.
Gresnigt, M.S.
Lachmandas, E.
Giamarellos-Bourboulis, E.J.
Kox, M.
Manjeri, G.R.
Wagenaars, J.A.L.
Cremer, O.L.
Leentjens, J.
Van Der Meer, A.J.
Van De Veerdonk, F.L.
Bonten, M.J.
Schultz, M.J.
Willems, P.H.G.M.
Pickkers, P.
Joosten, L.A.B.
Van Der Poll, T.
Netea, M.G.
Περιοδικό:
Nature Immunology
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
cytokine; lipopolysaccharide; metformin; recombinant gamma interferon; adenosine triphosphate; antifungal agent; cytokine; gamma interferon; lactic acid; nicotinamide adenine dinucleotide; transcriptome, adult; aerobic glycolysis; aerobic metabolism; aged; animal experiment; animal model; Article; Candida albicans; cell metabolism; controlled study; cytokine production; energy metabolism; Escherichia coli; female; fungemia; genetic transcription; glycolysis; host resistance; human; immune system; immunological parameters; immunological tolerance; immunoparalysis; inflammation; leukocyte; male; metabolism; mortality; mouse; nonhuman; oxidative phosphorylation; priority journal; sepsis; systemic mycosis; animal; aspergillosis; Candidiasis, Invasive; endotoxemia; energy metabolism; Escherichia coli infection; immunoblotting; immunology; innate immunity; leukocyte; macrophage; middle aged; monocyte; oxygen consumption; prospective study; sepsis; young adult, Adenosine Triphosphate; Adult; Animals; Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Cytokines; Endotoxemia; Energy Metabolism; Escherichia coli Infections; Female; Glycolysis; Humans; Immune Tolerance; Immunity, Innate; Immunoblotting; Interferon-gamma; Lactic Acid; Leukocytes; Lipopolysaccharides; Macrophages; Male; Mice; Middle Aged; Monocytes; NAD; Oxidative Phosphorylation; Oxygen Consumption; Prospective Studies; Sepsis; Transcriptome; Young Adult
