Neutrophil-derived reactive oxygen species and bystander tissue damage in inflammatory bowel disease.

Neutrophils (PMNs) are indispensable effectors of innate immunity whose oxidative and proteolytic capabilities permit rapid microbial containment at mucosal surfaces. Nowhere is this more functionally consequential than in the gastrointestinal tract, where PMN recruitment to the intestinal mucosa serves as both a critical antimicrobial safeguard and a primary driver of epithelial injury in inflammatory bowel diseases (IBD). Upon activation, PMNs deploy an intricate oxidative network centered on the phagocyte NADPH oxidase complex-derived superoxide and hydrogen peroxide in conjunction with the halogenating and nitrating chemistries catalyzed by myeloperoxidase (MPO). These pathways generate a rich repertoire of oxidants-including hypochlorous acid (HOCl), hypobromous acid, reactive nitrogen species, and secondary radical products-that interact with proteins, lipids, nucleic acids, and extracellular matrix components with distinct reaction kinetics and spatial preferences. Importantly, the magnitude, composition, and distribution of these oxidants shape tissue outcomes ranging from transient signaling alterations to epithelial barrier dysfunction and mutational injury contributing to dysplasia. Recent advances in redox proteomics, spatial transcriptomics, intravital imaging, and single-cell analyses have expanded our understanding of how PMN oxidative radical pathways operate within specific mucosal microenvironments and how their outputs intersect with epithelial repair pathways, the microbiome, innate immune crosstalk, and disease chronicity. These studies reveal that PMNs do not function as a uniform oxidative manner; rather, distinct subsets specialize in oxidative burst, extracellular trap formation, metabolic adaptation, or reparative functions. Together, these data emphasize that oxidative injury in IBD is not an unavoidable byproduct of inflammation but rather a dynamic, context-dependent process that with significant potential as a therapeutic target. In this review, we synthesize current knowledge of PMN oxidative radical biology with a focus on the gastrointestinal mucosa. We examine the architecture of PMN reactive oxygen species (ROS) systems, delineate mechanisms of oxidative tissue injury, integrate translational and microbiome implications, and evaluate therapeutic strategies aimed at reducing bystander damage while preserving essential host defense. Through this framework, we highlight future directions that may enable the development of selective redox-modulating therapies capable of restoring mucosal integrity without compromising antimicrobial function.