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


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.

DOI: 10.1038/ni.3398
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@article{Cheng2016BroadDI, title={Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis}, author={Shih-Chin Cheng and Brendon P. Scicluna and Rob J W Arts and Mark S Gresnigt and Ekta Lachmandas and Evangelos J Giamarellos-Bourboulis and Matthijs Kox and Ganesh R. Manjeri and Jori A. L. Wagenaars and Olaf L. Cremer and Jenneke Leentjens and Anne Jan van der Meer and Frank Leo van de Veerdonk and Marc Bonten and Marcus J. Schultz and Peter H G M Willems and Peter Pickkers and Leo A B Joosten and Tom S van der Poll and Mihai G. Netea}, journal={Nature Immunology}, year={2016}, volume={17}, pages={406-413} }