Neutrophil Extracellular Traps in Inflammatory Bowel Disease: Pathogenic Mechanisms and Clinical Translation

Abstract

The Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC) and Crohn's Disease (CD) are characterised by chronic non-resolving gut mucosal inflammation involving innate and adaptive immune responses. Neutrophils, usually regarded as first responders in inflammation, are a key presence in the gut mucosal inflammatory milieu in IBD. Here, we review the role of neutrophil extracellular trap (NET) formation as a potential effector disease mechanism. NETs are extracellular webs of chromatin, microbicidal proteins and oxidative enzymes that are released by neutrophils to contain pathogens. NETs contribute to the pathogenesis of several immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis; and recently, as a major tissue damaging process involved in the host response to severe acute respiratory syndrome coronavirus 2 infection. NETs are pertinent as a defence mechanism at the gut mucosal interphase exposed to high levels of bacteria, viruses and fungi. On the other hand, NETs can also potentiate and perpetuate gut inflammation. In this review, we discuss the broad protective vs. pathogenic roles of NETs, explanatory factors that could lead to an increase in NET formation in IBD and how NETs may contribute to gut inflammation and IBD-related complications. Finally, we summarise therapeutic opportunities to target NETs in IBD.

Keywords: CD; IBD; Immunology; Inflammation; Neutrophil Extracellular Traps; Neutrophils; UC.

Figure 1

Pathogenicprocesses of NETs in human diseases. Nϕs, neutrophils.

Figure 2

NETs in the gut and IBD. Inflamed UC gut mucosa and the presence of NETs (colocalization of MPO and s100a9 in crypt abscesses and subepithelium [arrowheads]). s100a9 is part of the calprotectin molecule. DAMPs, damage-associated molecular patterns; NΦs, neutrophils; PAMPs, pathogen-associated molecular patterns.