Epigenetic Biomarkers for Human Sepsis and Septic Shock: Insights from Immunosuppression

Abstract

<jats:p> Sepsis is a life-threatening condition that occurs when the body responds to an infection damaging its own tissues. Sepsis survivors sometimes suffer from immunosuppression increasing the risk of death. To our best knowledge, there is no ‘gold standard’ for defining immunosuppression except for a composite clinical end point. As the immune system is exposed to epigenetic changes during and after sepsis, research that focuses on identifying new biomarkers to detect septic patients with immunoparalysis could offer new epigenetic-based strategies to predict short- and long-term pathological events related to this life-threatening state. This review describes the most relevant epigenetic mechanisms underlying alterations in the innate and adaptive immune responses described in sepsis and septic shock, and their consequences for immunosuppression states, providing several candidates to become epigenetic biomarkers that could improve sepsis management and help predict immunosuppression in postseptic patients. </jats:p>

miRNA-23b as a biomarker of culture-positive neonatal sepsis

“…Another study reveals that miR-23b inhibition down-regulates the expression of programmed death ligand-1 (PD-L1) on splenic T lymphocytes of septic mice. This discovery opens up new therapeutic pathways in late stages of the septic phase (Beltrán-García et al 2020). Finally, another study demonstrates that miR-23b is an antiinflammatory factor that negatively regulates the inflammatory responses induced by lipopolysaccharide (LPS) by targeting metalloproteinase 10 (ADAM10) (Zhang et al 2019a).…”

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

“…Moreover, miRNAs have other features that make them optimal candidates as biomarkers, such as the fact they are present in biofluids, including blood, urine, and saliva, allowing relatively noninvasive sample collection [ 80 , 92 ]. In addition to their accessibility, miRNAs are highly stable in biofluids and in different biospecimens making them relatively easy to work with and analyze using different methods (i.e., small RNA sequencing, arrays, qPCR, and ddPCR) [ 93 – 96 ].…”

“…Its expression was correlated with mortality in septic patients [ 90 ] miR-155 miR-155 plays an essential role in neuroinflammation because it regulates the overexpression and activation of NF-κB and therefore induces neural pyroptosis through activation of the IL-1β signaling pathway Interestingly, its inhibition in microglia contributes to the development of endotoxin tolerance through an immune-homeostatic reaction. Therefore, it is expected that downregulation of miR-155 may protect microglia against LPS-induced inflammatory injury, which is frequent in septic infections [ 39 , 74 , 95 , 96 , 98 – 101 ] miR-27a miR-27a is able to inhibit microglia-produced inflammatory cytokines, including IL-6, IL-1β, and TNF-α and block the expression of TLR4 and IRAK4 [ 102 ] miR-210 miR-210 is an important regulator of hypoxia response through the control of many functions such as DNA repair, mitochondrial respiration, angiogenesis, and cell proliferation. Likewise, low miR-210 levels show neuroprotective effects on mice with hypoxic-ischemic encephalopathy, due to its capacity for activating microglia.…”

Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective

“…In this context, the dysregulation of innate and adaptive immunity is associated with harmful consequences, which, together with organ failure, lead to increased short- and long-term mortality in septic patients ( 46 ).…”