Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis

Abstract

BackgroundSepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation.MethodsBead arrays were used to compare global DNA methylation changes in patients with sepsis, non-infectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming.ResultsHere, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance.ConclusionWe have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction.

Differential Gene Expression in Circulating CD14+ Monocytes Indicates the Prognosis of Critically Ill Patients with Sepsis

“…RNA sequencing revealed a clear separation of samples from healthy individuals and samples from ICU patients (see Figure 3B). A recent study nicely demonstrated widespread changes in the methylome of circulating monocytes from septic patients with the acquisition of a tolerized phenotype and organ dysfunction [43].…”

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

“…Sepsis is defined as life-threatening organ dysfunction caused by a deregulated systemic immune response to infection. Interestingly, DNA methylation changes have been associated with sepsis in monocytes, which correlated with inflammatory signals [133]. Besides, chromatin modifications have been implicated in the regulation of the cellular immune/inflammatory responses in patients with sepsis [134].…”

B cell depletion and signs of sepsis-acquired immunodeficiency in bone marrow and spleen of COVID-19 deceased

“…This was reflected by an early increase of myeloid PD-L1 expression, lymphocytic apoptosis and macrophage anergy with loss of antigen-presenting capacity ( Hotchkiss and Nicholson, 2006 , Huang et al, 2014 , Landelle et al, 2010 ). Usually, sepsis acquired immunodeficiency is accompanied by cytokine-related T cell exhaustion, release of myeloid suppressor cells and epigenetically determined monocyte switch to endotoxin tolerance after bacterial stress ( Biswas and Lopez-Collazo, 2009 , Boomer et al, 2011 , Cheng et al, 2016 , Lorente-Sorolla et al, 2019 ). Thus, methylation-related predisposition for immune memory adaption may influence the highly variable outcome and affect later immunity in patients with severe bacterial co-infection of COVID-19 pneumonia to a varying extent.…”