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.

Perinatal inflammation influences but does not arrest rapid immune development in preterm babies

“…Our data highlight the influence of both the in utero environment and the postnatal clinical course on the developing immune profiles of preterm infants. Bacteria implicated in chorioamnionitis (such as E. coli) have also been shown to produce histone-modifying enzymes to down-regulate protein expression and there is increasing evidence that sepsis can induce epigenetic changes that alter immune responses 26,27 . We cannot exclude the potential confounder of GA in our data set as all of the stable babies were born at a later GA.…”

Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis

“…Clinical phenotype: Increased susceptibility to secondary infections in the blood and lungs [ 96 ] Persistence of septic shock with ≥2 organ dysfunctions after initial resuscitation treatment (Expert Opinion) Persistent immunosuppression determined by e.g. high PD-1, lymphopenia, low IgM levels, low HLA-DR expression on monocytes, expansion of MDSCs [ 111 , 124 – 126 ] (Expert Opinion) Clinical examples: nosocomial infections, secondary fungal infections (e.g. Aspergillosis), viral reactivation, insufficient clearance of primary infective focus, multi-morbid elderly patient (diabetes mellitus, liver disease, renal insufficiency, malnutrition), patients with viral (co-)reactivation [ 110 ] …”

Salmonella enterica serovar Typhi exposure elicits ex vivo cell-type-specific epigenetic changes in human gut cells

“…Epigenetic modifications, or marks including acetylation, methylation, phosphorylation, and ubiquitination, can alter gene activity, thereby regulating patterns of gene expression 10 , 11 . These processes are fundamental for the development and differentiation of distinct cell lineages in the body and can be modified by exogenous influences, such as environment and infectious diseases 11 – 14 .…”