De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease

Infiltrating neutrophils are key effector cells in inflammatory bowel disease (IBD) while providing antimicrobial defense and tissue restitution in the intestine. The complexity of neutrophil functions in local environments underscores our limited understanding of how their adaptation in tissues influences disease progression. Here, we demonstrate that neutrophils recruited in murine colitis and infection models, idiopathic IBD, and chronic granulomatous disease-associated IBD undergo extensive transcriptional reprogramming, resulting in the emergence of neutrophil populations that feature unique DUOX2 NADPH oxidase expression. Functional studies utilizing mice with myeloid and neutrophil specific DUOX2 inactivation reveal a vital and dichotomous role for this NADPH oxidase in both colitis and intestinal infection. Niche-directed reprogramming promoted a DUOX2-dependent chemokine and cytokine-rich intestinal environment that amplified and prolonged inflammatory responses, suggesting that selectively suppressing DUOX2 may constitute an anti-inflammatory strategy for IBD treatment. Altering spatiotemporal redox signaling by de novo expression of a ROS-generating enzyme represents an important feature for functional neutrophil diversification in disease, with implications for other neutrophil-driven diseases in specialized niches.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-05-06
DOI
https://doi.org/10.1073/pnas.2421747122
Citations
8
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
Field-Weighted Citation Impact
6.38

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article

De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease

Ioanna Tzani, Ulla G. Knaus, Colin Clarke, Glen A. Doherty et al.
8 citations
Proceedings of the National Academy of Sciences
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
6.38
article

De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease

Ioanna Tzani, Ulla G. Knaus, Colin Clarke, Glen A. Doherty, Vincent P. Kelly, Marina Ainciburu, Séamus Hussey, Alfonso Blanco, Yasutada Akiba, Jonathan D. Kaunitz, Stephen J. Lalor, Ashish Singh, Christa S. Zerbe, Kieran J. Wynne, Sajad A. Bhat, Billy Bourke
article en
8 citations

Abstract

Infiltrating neutrophils are key effector cells in inflammatory bowel disease (IBD) while providing antimicrobial defense and tissue restitution in the intestine. The complexity of neutrophil functions in local environments underscores our limited understanding of how their adaptation in tissues influences disease progression. Here, we demonstrate that neutrophils recruited in murine colitis and infection models, idiopathic IBD, and chronic granulomatous disease-associated IBD undergo extensive transcriptional reprogramming, resulting in the emergence of neutrophil populations that feature unique DUOX2 NADPH oxidase expression. Functional studies utilizing mice with myeloid and neutrophil specific DUOX2 inactivation reveal a vital and dichotomous role for this NADPH oxidase in both colitis and intestinal infection. Niche-directed reprogramming promoted a DUOX2-dependent chemokine and cytokine-rich intestinal environment that amplified and prolonged inflammatory responses, suggesting that selectively suppressing DUOX2 may constitute an anti-inflammatory strategy for IBD treatment. Altering spatiotemporal redox signaling by de novo expression of a ROS-generating enzyme represents an important feature for functional neutrophil diversification in disease, with implications for other neutrophil-driven diseases in specialized niches.

Proceedings of the National Academy of SciencesVol. 122(19)
University College Dublin (IE), National Institutes of Health (US), Royal College of Surgeons in Ireland (IE), University of California, Los Angeles (US), Trinity College (CA), Children's Health Ireland at Crumlin (IE), St. Vincent's University Hospital (IE), National Institute of Allergy and Infectious Diseases (US), Conway School of Landscape Design (US), National Institute for Bioprocessing Research and Training (IE), VA Greater Los Angeles Healthcare System (US)
Health Research Board, Science Foundation Ireland
Good health and well-being
Openalex Percentile: Top 3%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
6.38
DOIOpen Access PDFOpenAlex
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