Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections

[Display omitted] •ROS generated by NOX2, not mitochondria, play a crucial role in neutrophil-mediated elimination of clinical UPEC isolates.•NOX2-derived ROS regulate NF-κB-dependent inflammatory responses in UPEC-infected neutrophils via NRF2 signaling.•NOX2 promotes mucosal immunity and regulates NF-kB-dependent inflammation during experimental cystitis. The 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.