Cotzomi-Ortega, IsraelRosowski, Emily E.Wang, XinSanchez-Zamora, Yuriko I.Lopez-Torres, Jeimy M.Sanchez-Orellana, GamalielHan, RachelVásquez-Martínez, GabrielaAndrade, Gabriel MayoralBallash, GregoryCortado, HannaLi, BirongAli, YusufRascon, RaulRobledo-Avila, FrankPartida-Sanchez, SantiagoPérez-Campos, EduardoOlofsson-Sahl, PeterZepeda-Orozco, DianaSpencer, John DavidBecknell, BrianRuiz-Rosado, Juan de Dios2025-05-202025-05-202025Cotzomi-Ortega I, Rosowski EE, Wang X, et al. Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections. Mucosal Immunol. 2025;18(2):402-417. doi:10.1016/j.mucimm.2024.12.010https://hdl.handle.net/1805/48241The precise role of neutrophil-derived reactive oxygen species (ROS) in combating bacterial uropathogens during urinary tract infections (UTI) remains largely unexplored. In this study, we elucidate the antimicrobial significance of NADPH oxidase 2 (NOX2)-derived ROS, as opposed to mitochondrial ROS, in facilitating neutrophil-mediated eradication of uropathogenic Escherichia coli (UPEC), the primary causative agent of UTI. Furthermore, NOX2-derived ROS regulate NF-κB-mediated inflammatory responses in neutrophils against UPEC by inducing the release of nuclear factor erythroid 2-related factor 2 (Nrf2) from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Consistently, the absence of NOX2 (Cybb-/-) in mice led to uncontrolled bacterial infection associated with increased NF-κB signaling, heightened neutrophilic inflammation, and increased bladder pathology during cystitis. These findings underscore a dual role for neutrophil NOX2 in both eradicating UPEC and mitigating neutrophil-mediated inflammation in the urinary tract, revealing a previously unrecognized effector and regulatory mechanism in the control of UTI.en-USPublisher PolicyInnate immunityNADPH oxidaseNeutrophilsNrf2Urinary tract infectionUropathogenic Escherichia coliArticle