Exposure of Monocytic Cells to Lipopolysaccharide Induces Coordinated Endotoxin Tolerance, Mitochondrial Biogenesis, Mitophagy, and Antioxidant Defenses.
Widdrington, John D
Baudouin, Simon V
Rostron, Anthony J
Lovat, Penny E
Simpson, A John
Frontiers Media SA
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Widdrington, J. D., Gomez-Duran, A., Pyle, A., Ruchaud-Sparagano, M., Scott, J., Baudouin, S. V., Rostron, A. J., et al. (2018). Exposure of Monocytic Cells to Lipopolysaccharide Induces Coordinated Endotoxin Tolerance, Mitochondrial Biogenesis, Mitophagy, and Antioxidant Defenses.. Front Immunol, 9 2217. https://doi.org/10.3389/fimmu.2018.02217
In order to limit the adverse effects of excessive inflammation, anti-inflammatory responses are stimulated at an early stage of an infection, but during sepsis these can lead to deactivation of immune cells including monocytes. In addition, there is emerging evidence that the up-regulation of mitochondrial quality control mechanisms, including mitochondrial biogenesis and mitophagy, is important during the recovery from sepsis and inflammation. We aimed to describe the relationship between the compensatory immune and mitochondrial responses that are triggered following exposure to an inflammatory stimulus in human monocytic cells. Incubation with lipopolysaccharide resulted in a change in the immune phenotype of THP-1 cells consistent with the induction of endotoxin tolerance, similar to that seen in deactivated septic monocytes. After exposure to LPS there was also early evidence of oxidative stress, which resolved in association with the induction of antioxidant defenses and the stimulation of mitochondrial degradation through mitophagy. This was compensated by a parallel up-regulation of mitochondrial biogenesis that resulted in an overall increase in mitochondrial respiratory activity. These observations improve our understanding of the normal homeostatic responses that limit the adverse cellular effects of unregulated inflammation, and which may become ineffective when an infection causes sepsis.
Monocytes, Mitochondria, Humans, Lipopolysaccharides, Endotoxins, Immune Tolerance, Oxidative Stress, Organelle Biogenesis, THP-1 Cells, Mitophagy
JDW was funded by a Wellcome Trust Translational Medicine and Therapeutics Fellowship. PFC is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (101876/B/13/A)
External DOI: https://doi.org/10.3389/fimmu.2018.02217
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285347
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/