What is it about?
The presence of neutrophils in tissues is a hallmark of inflammation. In inflammatory bowel disease (IBD), infiltrating neutrophils act as first responders, limiting microbes from breaching the gut barrier and contributing to the resolution of inflammation. Yet, accumulation of highly activated neutrophils also perpetuates inflammation by generating reactive oxygen species (ROS) and by releasing proteases and neutrophil extracellular traps. In accord, neutrophil biomarkers are used as clinical predictors of IBD disease activity. We show here that neutrophils in the inflamed gut amplify their oxidative repertoire, expressing the H2O2-producing enzyme DUOX2. Preclinical colitis models confirmed that DUOX2, but not the well-known phagocyte oxidase, mediates inflammation and tissue injury.
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Photo by Pawel Czerwinski on Unsplash
Why is it important?
Current IBD therapy includes anti-inflammatory drugs, immunosuppressants, and biologics. These approaches help manage symptoms and reduce flare-ups, but often have significant limitations. There is a pressing need for new drug targets and therapies that are more effective, longer-lasting, and have fewer side effects to improve outcomes for people living with IBD. Our work identifies DUOX2 as a potential drug target for suppressing acute neutrophil-driven inflammation without compromising antimicrobial defense.
Perspectives
This project would not have succeeded without the support of clinicians and IBD patients. We did not set out to find a new IBD drug target or a new source for oxidants in neutrophils. We challenged prevailing scientific dogma and let our curiosity lead the way when patient tissues showed unexpected results. Excitingly, similar phenotypic changes in neutrophil subsets also occur in other inflammatory diseases, suggesting broader patterns and new directions in inflammatory disease.
Ashish Singh
University College Dublin
Read the Original
This page is a summary of: De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease, Proceedings of the National Academy of Sciences, May 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2421747122.
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