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

Abstract

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.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Cotzomi-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.2024.12.010
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Mucosal Immunology
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Author's manuscript
Full Text Available at
This item is under embargo {{howLong}}