The Paradox of NET Involvement in the Pathogenesis of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC), are defined by chronic, non-resolving inflammation of the intestinal mucosa. Neutrophils are the first responders in inflammation, executing various effector functions, including chemotaxis, phagocytosis, degranulation and the release of cytokines, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). Amongst all neutrophil functions, emerging evidence increasingly suggests that NET release may be particularly relevant in underpinning the pathogenesis of IBD. NETs are extracellular structures composed of chromatin, antimicrobial proteins, and oxidative enzymes released by neutrophils to trap and neutralize pathogens. In this review, we discuss the protective roles of NETs in intestinal health and how, under tight physiological regulation, they can prevent pathogenic invasion, exert anti-inflammatory effects, and play an important role in wound healing and intestinal tissue repair. Conversely, we consider how inflammation-driven changes in neutrophil activation, phenotype and immunometabolism can cause dysregulation in NET production and clearance and lead to harmful intestinal effects that can prolong intestinal and chronic inflammation in IBD. Specifically, we explore how uncontrolled NET production can damage intestinal epithelial integrity, increase bacterial translocation and increase thromboembolic risk, ultimately linking NETs to the pro-inflammatory pathogenesis of IBD.