Epigenetics in Sepsis: Understanding Its Role in Endothelial Dysfunction, Immunosuppression, and Potential Therapeutics

Abstract

Sepsis has a complex pathophysiology in which both excessive and refractory inflammatory responses are hallmark features. Pro-inflammatory cytokine responses during the early stages are responsible for significant endothelial dysfunction, loss of endothelial integrity, and organ failure. In addition, it is now well-established that a substantial number of sepsis survivors experience ongoing immunological derangement and immunosuppression following a septic episode. The underpinning mechanisms of these phenomena are incompletely understood yet they contribute to a significant proportion of sepsis-associated mortality. Epigenetic mechanisms including DNA methylation, histone modifications, and non-coding RNAs, have an increasingly clear role in modulating inflammatory and other immunological processes. Recent evidence suggests epigenetic mechanisms are extensively perturbed as sepsis progresses, and particularly play a role in endothelial dysfunction and immunosuppression. Whilst therapeutic modulation of the epigenome is still in its infancy, there is substantial evidence from animal models that this approach could reap benefits. In this review, we summarize research elucidating the role of these mechanisms in several aspects of sepsis pathophysiology including tissue injury and immunosuppression. We also evaluate pre-clinical evidence for the use of "epi-therapies" in the treatment of poly-microbial sepsis.

Keywords: endothelial dysfunction; epigenetics; histone deacetylase inhibitors; immunosuppression; sepsis.

Figure 1

(A) Histone modifications: The negative charge of DNA allows it to bind tightly to positively charged histone proteins. DNA wraps around octomers of histone proteins and forms discrete units known as nucleosomes, the basis of chromatin. The overall structure and openness of chromatin is dictated by chemical modifications of the N terminal amino acid tails of the histone proteins. Chemical modifications include acetylation, methylation, phosphorylation, SUMOylation, citrullination, and ADP-ribosylation. (B) CpG methylation: The majority of cytosines found in cytosine-guanine dinucleotides (gray circles) are methylated. CpG-rich sections of the genome (CpG islands) occurs in areas requiring transcriptional control e.g., retrotransposons and gene promotors. Here, methylation status is more dynamic, with some hypomethylated CpGs (white circles) facilitating promotor accessibility and gene transcription. (C) Small non-coding RNAs interact with complementary sequences in DNA and on mRNA to interfere with gene transcription and translation respectively. A well-known species of small RNAs are microRNAs. Mature single stranded microRNAs molecules (21–24 nt long) are incorporated into the RNA induced silencing complex (RISC) and then bind to a complementary sequence in the 3'UTRs of mRNA molecules. This binding inhibits mRNA translation and results in either mRNA degradation or storage.