Abstract
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.
Highlights
Inflammatory bowel diseases (IBD) comprise Crohn’s disease (CD) and ulcerative colitis (UC)that affect over 3.5 million people worldwide [1]
Since neutrophils are the first immune cells recruited to the colon during colitis, we reasoned that the infiltrating neutrophils are activated, which would lead to neutrophil extracellular trap (NET) formation [14]
We showed that NET formation impairs the intestinal epithelial permeability and function, leading to an increased translocation of luminal bacteria in vivo
Summary
That affect over 3.5 million people worldwide [1]. These diseases are characterized by aberrant immune responses against commensal microorganisms, leading to chronic intestinal inflammation [2]. Genetic polymorphisms and environmental cues can both result in decreased gut epithelium integrity and increase intestinal permeability to innocuous microbiota. This predisposition eventually leads to abnormal innate and adaptive immune responses and underpins the pathogenesis of IBD [2,4]. Upon the initiation of the inflammatory response, circulating neutrophils transmigrate into the intestinal mucosa [5]. Neutrophil migration into the inflamed tissues is an essential process of the immune defense, mucosal healing, and resolution of inflammation [6,7], increased
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
