Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

Abstract

<jats:p>Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria, and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.</jats:p>

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“… 42 , 43 NETs are found to accumulate in inflamed intestinal mucosa from patients with active UC and sustain inflammatory signals. 44 Recent studies also demonstrated the pathological role of NETs in inflamed mucosa, such as impairing intestinal barrier function, 45 and inducing intestinal damage and thrombotic tendency. 24 PMA is an artificial stimuli to profoundly induce neutrophil production of extracellular traps.…”

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“…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 ].…”

“…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 ].…”

“…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 ].…”