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

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.

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis

“…NETs have been implicated in many gastrointestinal diseases including inflammatory bowel diseases (IBDs) [ 39 , 40 , 41 ], liver disease [ 35 ], and acute pancreatitis [ 42 , 43 , 44 ]. A chronic abiding repetitive event of inflammation in intestinal epithelium is portrayed as IBD [ 39 ].…”

“…NETs have been implicated in many gastrointestinal diseases including inflammatory bowel diseases (IBDs) [ 39 , 40 , 41 ], liver disease [ 35 ], and acute pancreatitis [ 42 , 43 , 44 ]. A chronic abiding repetitive event of inflammation in intestinal epithelium is portrayed as IBD [ 39 ]. Aberrant NET accumulation and the deterioration of inflamed intestinal barrier integrity can be correlated with IBD [ 39 ], as in ulcerative colitis (UC) [ 40 ].…”

“…A chronic abiding repetitive event of inflammation in intestinal epithelium is portrayed as IBD [ 39 ]. Aberrant NET accumulation and the deterioration of inflamed intestinal barrier integrity can be correlated with IBD [ 39 ], as in ulcerative colitis (UC) [ 40 ]. Neutrophils and NET-associated molecules are found in abundance in both colonic biopsies of UC [ 45 , 46 ] and Crohn’s disease (CD) [ 41 ], which indicate intestinal inflammatory aggravation, epithelial exasperation, and elevated thrombotic impulse [ 47 ].…”

“…Administration of dextran sulfate sodium (DSS) [ 36 , 46 ] or 2,4,6-trinitrobenzene sulfonic acid (TNBS) [ 40 ] can induce murine UC, principally by disrupting intestinal epithelial barrier and eliciting a number of chronic immunologic responses. In the mouse model, increased DSS consumption can elevate the plasma level of extracellular DNA (ecDNA) in the form of NETs, which in turn induces UC [ 39 ]. The elevated response is correlated with the amplitude of disease severity and relative proportion of cells undergoing NETosis.…”

“…The elevated response is correlated with the amplitude of disease severity and relative proportion of cells undergoing NETosis. However, the initial administration of protein-arginine deaminase type 4 (PAD4) inhibitors, Cl-amidine and streptonigrin can curb the formation of NETs, and in turn decrease the plasma ecDNA level in UC [ 39 ]. Some other studies have reported that the systemic administration of DNase can lead to amelioration of DSS-induced colitis by dissolving NETs [ 39 , 47 ].…”