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

## TL;DR

This review explores how neutrophil extracellular traps (NETs) can both protect and harm the intestines, contributing to the chronic inflammation seen in inflammatory bowel disease.

## Contribution

The paper highlights the dual role of NETs in intestinal health and disease, offering new insights into their paradoxical involvement in IBD.

## Key findings

- NETs can prevent pathogenic invasion and aid in intestinal tissue repair under normal conditions.
- Dysregulated NET production in IBD can damage the intestinal epithelium and increase bacterial translocation.
- Uncontrolled NETs are linked to prolonged inflammation and thromboembolic risks in IBD.

## Abstract

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.