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

  • Mucosal Immunol. 2024 Dec 20:S1933-0219(24)00133-8. doi: 10.1016/j.mucimm.2024.12.010.
Israel Cotzomi-Ortega  1 ,  Emily E Rosowski  2 ,  Xin Wang  1 ,  Yuriko I Sanchez-Zamora  1 ,  Jeimy M Lopez-Torres  1 ,  Gamaliel Sanchez-Orellana  1 ,  Rachel Han  3 ,  Gabriela Vásquez-Martínez  1 ,  Gabriel Mayoral Andrade  4 ,  Gregory Ballash  5 ,  Hanna Cortado  1 ,  Birong Li  1 ,  Yusuf Ali  1 ,  Raul Rascon  6 ,  Frank Robledo-Avila  6 ,  Santiago Partida-Sanchez  6 ,  Eduardo Pérez-Campos  7 ,  Peter Olofsson-Sahl  8 ,  Diana Zepeda-Orozco  9 ,  John David Spencer  9 ,  Brian Becknell  10 ,  Juan de Dios Ruiz-Rosado  11
Affiliations
  • 1. Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
  • 2. Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA; Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, SC 29634, USA.
  • 3. Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health, Division of Neonatology, Indianapolis, IN, USA.
  • 4. Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Center for Research in Medicine, National Autonomous University of Mexico-Autonomous University Benito Juárez of Oaxaca (UNAM-UABJO), Faculty of Medicine and Surgery, Autonomous University Benito Juárez of Oaxaca, Oaxaca 68020, Mexico.
  • 5. Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, OH, USA.
  • 6. Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
  • 7. National Technological Institute of Mexico, Oaxaca, Oaxaca 68030, Mexico.
  • 8. Pronoxis AB, SE-461 33 Trollhättan, Sweden; University West, Department of Health Sciences, SE-461 86 Trollhättan, Sweden.
  • 9. Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's Hospital, Columbus, OH 43215, USA.
  • 10. Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's Hospital, Columbus, OH 43215, USA. Electronic address: [email protected].
  • 11. Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's Hospital, Columbus, OH 43215, USA. Electronic address: [email protected].
PMID: 39710133 DOI: 10.1016/j.mucimm.2024.12.010
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.

Keywords
Innate Immunity; NADPH oxidase; Neutrophils; Nrf2; Urinary tract infection; Uropathogenic Escherichia coli.
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