Abstract
Introduction
Patients with sepsis exhibit significant, persistent immunologic dysfunction. Evidence
supports the hypothesis that epigenetic regulation of key cytokines plays an important
role in this dysfunction. In sepsis, circulating microvesicles (MVs) containing elevated
levels of DNA methyltransferase (DNMT) mRNA cause gene methylation and silencing in
recipient cells. We sought to examine the functional role of MV DNMT proteins in this
immunologic dysfunction.
Methods
In total, 33 patients were enrolled within 24 h of sepsis diagnosis (23 sepsis, 10
critically ill controls). Blood and MVs were collected on days 1, 3, and 5 of sepsis,
and protein was isolated from the MVs. Levels of DNMT protein and activity were quantified.
MVs were produced in vitro by stimulating naïve monocytes with lipopolysaccharide. Methylation was assessed
using bisulfate site-specific qualitative real-time polymerase chain reaction.
Results
The size of MVs in the patients with sepsis decreased from days 1 to 5 compared to
the control group. Circulating MVs contained significantly higher levels of DNMT 1
and 3A, protein. We recapitulated the production of these DNMT-containing MVs in vitro by treating monocytes with lipopolysaccharide. We found that exposing naïve monocytes
to these MVs resulted in increased promoter methylation of tumor necrosis factor alpha.
Conclusions
An analysis of the isolated MVs revealed higher levels of DNMT proteins in septic
patients than those in nonseptic patients. Exposing naïve monocytes to DNMT-containing
MVs produced in vitro resulted in hypermethylation of tumor necrosis factor alpha, a key cytokine implicated
in postsepsis immunosuppression. These results suggest that DNMT-containing MVs cause
epigenetic changes in recipient cells. This study highlights a novel role for MVs
in the immune dysfunction of patients with sepsis.
Keywords
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References
- Sepsis: pathophysiology and clinical management.BMJ. 2016; 353: i1585
- The pathogenesis of sepsis and potential therapeutic targets.Int J Mol Sci. 2019; 20: E5376
- Cytokine storm and sepsis disease pathogenesis.Semin Immunopathol. 2017; 39: 517-528
- Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome.Crit Care Med. 2017; 45: 253-262
- Innate immunity in the persistent inflammation, immunosuppression, and catabolism syndrome and its implications for therapy.Front Immunol. 2018; 9: 595
- Immunosuppression in patients who die of sepsis and multiple organ failure.JAMA. 2011; 306: 2594-2605
- Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care.J Trauma Acute Care Surg. 2012; 72: 1491-1501
- Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets.Int Immunopharmacol. 2020; 89: 107087
- The immune system’s role in sepsis progression, resolution, and long-term outcome - Delano - 2016 - Immunological Reviews - Wiley Online Library.https://onlinelibrary-wiley-com.proxy.lib.ohio-state.edu/doi/full/10.1111/imr.12499?sid=nlm%3ApubmedDate: 2021Date accessed: April 11, 2021
- The immunosuppressive face of sepsis early on intensive care unit—A large-scale microarray meta-analysis.PLoS One. 2018; 13: e0198555
- Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis.JAMA. 2019; 321: 2003
- The Third international Consensus definitions for sepsis and septic shock (Sepsis-3).JAMA. 2016; 315: 801
- Biomarker evidence of the persistent inflammation, immunosuppression and catabolism syndrome (PICS) in chronic critical illness (CCI) after surgical sepsis.Ann Surg. 2021; 274: 664-673
- Dysregulated immunity and immunotherapy after sepsis.J Clin Med. 2021; 10: 1742
- Long-term outcomes after critical illness: recent insights.Crit Care. 2021; 25: 108
- Epigenetic regulation in sepsis, role in pathophysiology and therapeutic perspective.Front Med. 2021; 8: 685333
- Circulating extracellular vesicle content reveals de novo DNA methyltransferase expression as a molecular method to predict septic shock.J Extracell Vesicles. 2019; 8: 1669881
- Proteomic pathway analysis of monocyte-derived exosomes during surgical sepsis identifies immunoregulatory functions.Surg Infect. 2020; 21: 101-111
- Epigenetics of Sepsis.Crit Care Med. 2020; 48: 745-756
- Epigenetic regulation of tumor necrosis factor Alpha.Mol Cell Biol. 2007; 27: 5147-5160
- DNA methylation and chromatin – unraveling the tangled web.Oncogene. 2002; 21: 5361-5379
- Extracellular vesicle proteins associated with systemic vascular events correlate with heart failure: an observational study in a dyspnoea cohort.PLoS One. 2016; 11: e0148073
- Exosomes in sepsis.Front Immunol. 2020; 11: 2140
- Minimal information for studies of extracellular vesicles 2018: a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.J Extracell Vesicles. 2018; 7: 1535750
- The EpiTect Methyl qPCR Assay as novel age estimation method in forensic biology.Forensic Sci Int. 2016; 264: 132-138
- Circulating microparticles, blood cells, and endothelium induce procoagulant activity in sepsis through phosphatidylserine exposure.Shock. 2016; 45: 299-307
- Epigenetic regulation of monocyte and macrophage function.Antioxid Redox Signal. 2016; 25: 758-774
- Exosomal transfer of DNA methyl-transferase mRNA induces an immunosuppressive phenotype in human monocytes.Shock. 2022; 57: 218-227
- Inhibiting DNA methylation improves survival in severe sepsis by regulating NF-KB.Front Immunol. 2020; 11: 1360
- Procainamide inhibits DNA methylation and alleviates multiple orgran dysfunction in rates with endotoxemic shock.PLoS One. 2016; 11: e0163690
Article info
Publication history
Published online: November 22, 2022
Accepted:
October 16,
2022
Received in revised form:
August 29,
2022
Received:
April 4,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
