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Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells.
Mediators Inflamm. 2020; 2020:8294342.MI

Abstract

Sepsis is associated with a strong inflammatory reaction triggering a complex and prolonged immune response. Septic patients have been shown to develop sustained immunosuppression due to a reduced responsiveness of leukocytes to pathogens. Changes in cellular metabolism of leukocytes have been linked to this phenomenon and contribute to the ongoing immunological derangement. However, the underlying mechanisms of these phenomena are incompletely understood. In cell culture models, we mimicked LPS tolerance conditions to provide evidence that epigenetic modifications account for monocyte metabolic changes which cause immune paralysis in restimulated septic monocytes. In detail, we observed differential methylation of CpG sites related to metabolic activity in human PBMCs 18 h after septic challenge. The examination of changes in immune function and metabolic pathways was performed in LPS-tolerized monocytic THP-1 cells. Passaged THP-1 cells, inheriting initial LPS challenge, presented with dysregulation of cytokine expression and oxygen consumption for up to 7 days after the initial LPS treatment. Proinflammatory cytokine concentrations of TNFα and IL1β were significantly suppressed following a second LPS challenge (p < 0.001) on day 7 after first LPS stimulation. However, the analysis of cellular metabolism did not reveal any noteworthy alterations between tolerant and nontolerant THP-1 monocytes. No quantitative differences in ATP and NADH synthesis or participating enzymes of energy metabolism occurred. Our data demonstrate that the function and epigenetic modifications of septic and tolerized monocytes can be examined in vitro with the help of our LPS model. Changes in CpG site methylation and monocyte function point to a correlation between epigenetic modification in metabolic pathways and reduced monocyte function under postseptic conditions.

Authors+Show Affiliations

Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, Germany.Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32617075

Citation

Weisheit, Christina K., et al. "Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells." Mediators of Inflammation, vol. 2020, 2020, p. 8294342.
Weisheit CK, Klüners A, Wild L, et al. Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells. Mediators Inflamm. 2020;2020:8294342.
Weisheit, C. K., Klüners, A., Wild, L., Casalter, A., Heilmann-Heimbach, S., Sivalingam, S., Kleiner, J. L., Ehrentraut, S. F., Hoeft, A., Frede, S., & Ehrentraut, H. (2020). Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells. Mediators of Inflammation, 2020, 8294342. https://doi.org/10.1155/2020/8294342
Weisheit CK, et al. Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells. Mediators Inflamm. 2020;2020:8294342. PubMed PMID: 32617075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells. AU - Weisheit,Christina K, AU - Klüners,Alexandra, AU - Wild,Lennart, AU - Casalter,Alexandra, AU - Heilmann-Heimbach,Stefanie, AU - Sivalingam,Sugirthan, AU - Kleiner,Jan L, AU - Ehrentraut,Stefan F, AU - Hoeft,Andreas, AU - Frede,Stilla, AU - Ehrentraut,Heidi, Y1 - 2020/06/13/ PY - 2020/02/11/received PY - 2020/05/05/revised PY - 2020/05/11/accepted PY - 2020/7/4/entrez PY - 2020/7/4/pubmed PY - 2020/7/4/medline SP - 8294342 EP - 8294342 JF - Mediators of inflammation JO - Mediators Inflamm. VL - 2020 N2 - Sepsis is associated with a strong inflammatory reaction triggering a complex and prolonged immune response. Septic patients have been shown to develop sustained immunosuppression due to a reduced responsiveness of leukocytes to pathogens. Changes in cellular metabolism of leukocytes have been linked to this phenomenon and contribute to the ongoing immunological derangement. However, the underlying mechanisms of these phenomena are incompletely understood. In cell culture models, we mimicked LPS tolerance conditions to provide evidence that epigenetic modifications account for monocyte metabolic changes which cause immune paralysis in restimulated septic monocytes. In detail, we observed differential methylation of CpG sites related to metabolic activity in human PBMCs 18 h after septic challenge. The examination of changes in immune function and metabolic pathways was performed in LPS-tolerized monocytic THP-1 cells. Passaged THP-1 cells, inheriting initial LPS challenge, presented with dysregulation of cytokine expression and oxygen consumption for up to 7 days after the initial LPS treatment. Proinflammatory cytokine concentrations of TNFα and IL1β were significantly suppressed following a second LPS challenge (p < 0.001) on day 7 after first LPS stimulation. However, the analysis of cellular metabolism did not reveal any noteworthy alterations between tolerant and nontolerant THP-1 monocytes. No quantitative differences in ATP and NADH synthesis or participating enzymes of energy metabolism occurred. Our data demonstrate that the function and epigenetic modifications of septic and tolerized monocytes can be examined in vitro with the help of our LPS model. Changes in CpG site methylation and monocyte function point to a correlation between epigenetic modification in metabolic pathways and reduced monocyte function under postseptic conditions. SN - 1466-1861 UR - https://www.unboundmedicine.com/medline/citation/32617075/Sustained_Immunoparalysis_in_Endotoxin-Tolerized_Monocytic_Cells L2 - https://doi.org/10.1155/2020/8294342 DB - PRIME DP - Unbound Medicine ER -
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