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

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

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: brian.becknell2@nationwidechildrens.org.
  • 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: Juandedios.ruizrosado@nationwidechildrens.org.
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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