Extracellular DNA Correlates with Intestinal Inflammation in Chemically Induced Colitis in Mice.

Martin Maronek,David Smolak,Roman Gardlik,Barbora Cechova,Barbora Gromova,Robert Liptak,Tomas Szemes,Michal Pastorek,Maria Harsanyova,Jana Harsanyiova,Alzbeta Kralova Trancikova,Jan Radvanszky,Jaroslav Budis,Barbora Konecna

doi:10.3390/cells10010081

Abstract

Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.

Highlights

Inflammatory bowel disease (IBD) is characterized as a group of chronic inflammatory diseases such as ulcerative colitis or Crohn’s disease (CD) with long-lasting recurrent inflammation of intestinal epithelium
Our results have shown that the concentration of total extracellular DNA (ecDNA) in plasma rises with increasing inflammation
This rise was accompanied by both increased endoscopic score and increased percentage of neutrophils undergoing NETosis

Summary

Introduction

Inflammatory bowel disease (IBD) is characterized as a group of chronic inflammatory diseases such as ulcerative colitis or Crohn’s disease (CD) with long-lasting recurrent inflammation of intestinal epithelium. Given the fact that cell death usually occurs physiologically (e.g., apoptosis), a certain base-line ecDNA concentration can be measured even under physiological conditions [7,8] It appears that ecDNA from any source can be immunogenic because it has been shown to bind the toll-like receptor 9 [9] which in turn causes the activation of the cascade leading to the innate inflammatory response [10,11]. To this reason, ecDNA can be perceived as a marker of inflammation in a number of pathologies and diseases including sepsis [12,13,14], multiple trauma [15] or obesity [16]. This discrepancy further highlights that the role of ecDNA in inflammation has not been adequately described

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