Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections
Israel Cotzomi-Ortega, Emily E. Rosowski, Xin Wang, Yuriko I. Sánchez-Zamora, Jeimy M Lopez-Torres, Gamaliel Sanchez-Orellana, Rachel Han, Gabriela Vásquez Martínez, Gabriel Mayoral Andrade, Gregory A. Ballash, Hanna H. Cortado, Birong Li, Yusuf Ali, Raúl Rascón, Frank Robledo‐Avila, Santiago Partida-Sanchez, Eduardo Pérez‐Campos, Peter Olofsson, Diana Zepeda‐Orozco, John David Spencer, Brian Becknell, Juan de Dios Ruiz‐Rosado
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.