Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective

Abstract

Sepsis is characterized by an initial hyperinflammatory response, with intense cell activation and cytokine storm. In parallel, a prolonged compensatory anti-inflammatory response, known as immunological tolerance, can lead to immunosuppression. Clinically, this condition is associated with multiple organ failure, resulting in the patient's death. The mechanisms underlying the pathophysiology of sepsis are not yet fully understood, but evidence is strong showing that epigenetic changes, including DNA methylation and post-translational modifications of histones, modulate the inflammatory response of sepsis. During the onset of infection, host cells undergo epigenetic changes that favor pathogen survival. Besides, epigenetic changes in essential genes also orchestrate the patient's inflammatory response. In this review, we gathered studies on sepsis and epigenetics to show the central role of epigenetic mechanisms in various aspects of the pathogenesis of sepsis and the potential of epigenetic interventions for its treatment.

Keywords: DNA methylation; chromatin remodeling; epigenetics; histone modification; sepsis.

Figure 1

Schematic representation of epigenetic changes in the mononuclear cell. The chromosome is composed of chromatin, a complex formed by DNA and nucleosomes, and the core is formed by an octamer of histones. Both DNA and histones can suffer the action of catalyzing enzymes of chemical groups that influence the chromatin structure, affecting gene expression. K, lysine; HATs, histone acetyltransferases; HDACs, histone deacetylases; HMTs, histone methyltransferases; HDMs, histone demethylases; DNMTs, DNA methyltransferases.

Figure 2

Epigenetic modifications during infection. Pathogen recognition by PRR triggers cascades of intracellular signaling activating inflammatory mediators which induces dynamic changes in chromatin through epigenetic mechanisms, leading to increased or decreased gene activation. The pathogen can also directly alter chromatin through the influence of epigenetic modifiers. These epigenetic alterations (yellow background) may modulate the inflammatory response (pink background). Sepsis induces profound changes in gene expression involved in the inflammatory process and host defense. Epigenetic modifications play a central role in its regulation as evidenced by the presence of differentially methylated CpG islands, several modifications of histones with effects on gene activation (H3K4me, H3K9ac) and repression (H3K27me3, H3K9me3), and the presence of differentially expressed ncRNAs. PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDM, histone demethylase; HMT, histone methyltransferases; ncRNA, non-coding RNA.