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Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells
Christina K Weisheit1, Alexandra Klüners1, Lennart Wild1
1Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany.
Mediators of Inflammation
|July 4, 2020
Summary
Epigenetic modifications in monocytes after sepsis contribute to immune paralysis by altering metabolic pathways, even without direct metabolic changes. This study reveals a link between CpG methylation and reduced monocyte function post-sepsis.
Area of Science:
- Immunology
- Cellular Metabolism
- Epigenetics
Background:
- Sepsis triggers a strong inflammatory response and prolonged immunosuppression, characterized by reduced leukocyte responsiveness.
- Cellular metabolism changes in leukocytes are implicated in sepsis-induced immune derangement, but mechanisms remain unclear.
- Epigenetic modifications are increasingly recognized as key regulators of immune cell function.
Purpose of the Study:
- To investigate the role of epigenetic modifications in monocyte metabolic changes during sepsis-induced immune paralysis.
- To explore the correlation between CpG methylation, metabolic pathways, and monocyte function in a sepsis model.
- To analyze changes in immune function and metabolic pathways in lipopolysaccharide (LPS)-tolerized monocytic THP-1 cells.
Main Methods:
- Mimicked LPS tolerance conditions in cell culture to model septic immune responses.
- Analyzed differential methylation of CpG sites in human peripheral blood mononuclear cells (PBMCs) post-septic challenge.
- Examined immune function (cytokine expression) and cellular metabolism (oxygen consumption, ATP/NADH synthesis) in LPS-tolerized THP-1 cells.
Main Results:
- Differential CpG methylation related to metabolic activity was observed in PBMCs 18 hours after septic challenge.
- LPS-tolerized THP-1 cells showed dysregulated cytokine expression and oxygen consumption for up to 7 days.
- Proinflammatory cytokine concentrations (TNFα, IL1β) were significantly suppressed upon restimulation.
- No significant alterations in cellular metabolism, including ATP and NADH synthesis, were found between tolerant and non-tolerant cells.
Conclusions:
- Epigenetic modifications, specifically CpG methylation in metabolic pathways, correlate with reduced monocyte function in post-septic conditions.
- The study provides an in vitro model to examine epigenetic modifications and function of septic monocytes.
- While direct metabolic changes were not observed, epigenetic alterations appear to mediate immune paralysis in sepsis.
