Abstract
Mitochondrial DNA (mtDNA) plays a vital role as a damage-associated molecular pattern in sepsis being able to shape the immune response. Since pathogen recognition receptors of innate immune cells are activated by demethylated DNA only, we set out to investigate the amount of DNA methyltransferase 1 (DNMT1) in mitochondria and the extent of mtDNA methylation in a human endotoxin model. Peripheral blood mononuclear cells of 20 healthy individuals were isolated from whole blood and stimulated with lipopolysaccharide (LPS) for 48 h. Subsequently, DNMT1 protein abundance was assessed in whole cells and a mitochondrial fraction. At the same time, methylation levels of mtDNA were quantified, and cytokine expression in the supernatant was measured. Despite increased cellular expression of DNMT1 after LPS stimulation, the degree of mtDNA methylation slightly decreased. Strikingly the mitochondrial protein abundance of DNMT1 was reduced by 50% in line with the lower degree of mtDNA methylation. Although only modest alterations were seen in the degree of mtDNA methylation, these strongly correlated with IL-6 and IL-10 expression. Our data may hint at a protein import problem for DNMT1 into the mitochondria under LPS stimulation and suggest a role of demethylated mtDNA in the regulation of the inflammatory immune response.
Highlights
Sepsis is a highly complex immunological syndrome and one of the leading causes of death world-wide, affecting millions each year
Given that the function of DNA methyltransferase 1 (DNMT1) is thought to be maintaining the methylation pattern [19] a reduced mitochondrial abundance of this enzyme could lead to a reduced Mitochondrial DNA (mtDNA) methylation
We found that cellular expression of DNMT1 increased upon LPS stimulation
Summary
Sepsis is a highly complex immunological syndrome and one of the leading causes of death world-wide, affecting millions each year. In appreciation of our growing pathophysiological understanding, sepsis was redefined in 2016 as an acute organ dysfunction caused by a dysregulated immune response [1]. The improper interaction between inflammation and anti-inflammation contributing to a harmful immune reaction may represent a key element in sepsis pathology, but clear insights explaining this imbalance are still elusive. Mitochondrial DNA (mtDNA), not least because of its bacterial origin, is discussed as potent DAMP able to aggravate inflammatory response [5,6]. It has been described with strong anti-inflammatory patterns [7], which indicates a potential key role of mtDNA in
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