NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression

Chetanchandra S Joshi; Amy Mora; Paul A Felder; Indira U Mysorekar

doi:10.1016/j.celrep.2021.109856

NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression

Cell Rep. 2021 Oct 19;37(3):109856. doi: 10.1016/j.celrep.2021.109856.

Authors

Chetanchandra S Joshi¹, Amy Mora², Paul A Felder², Indira U Mysorekar³

Affiliations

¹ Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA.
³ Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].

PMID: 34686330
DOI: 10.1016/j.celrep.2021.109856

Abstract

Uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs) by invading urothelial cells. In response, the host mounts an inflammatory response to expel bacteria. Here, we show that the NF-E2-related factor 2 (NRF2) pathway is activated in response to UPEC-triggered reactive oxygen species (ROS) production. We demonstrate the molecular sequence of events wherein NRF2 activation in urothelial cells reduces ROS production, inflammation, and cell death, promotes UPEC expulsion, and reduces the bacterial load. In contrast, loss of NRF2 leads to increased ROS production, bacterial burden, and inflammation, both in vitro and in vivo. NRF2 promotes UPEC expulsion by regulating transcription of the RAB-GTPase RAB27B. Finally, dimethyl fumarate, a US Food and Administration-approved NRF2 inducer, reduces the inflammatory response, increases RAB27B expression, and lowers bacterial burden in urothelial cells and in a mouse UTI model. Our findings elucidate mechanisms underlying the host response to UPEC and provide a potential strategy to combat UTIs.

Keywords: ARE elements; HMOX1; KEAP1; NQO1; UPEC; autophagy; bladder; dimethyl fumarate; oxidative stress; p62; urinary tract infection; urothelium.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology
Bacterial Load
Cell Line, Tumor
Dimethyl Fumarate / pharmacology
Escherichia coli Infections / drug therapy
Escherichia coli Infections / genetics
Escherichia coli Infections / metabolism*
Escherichia coli Infections / microbiology
Female
HEK293 Cells
Host-Pathogen Interactions
Humans
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-E2-Related Factor 2 / agonists
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Oxidative Stress
Reactive Oxygen Species / metabolism*
Signal Transduction
Urinary Tract Infections / drug therapy
Urinary Tract Infections / genetics
Urinary Tract Infections / metabolism*
Urinary Tract Infections / microbiology
Uropathogenic Escherichia coli / pathogenicity*
Urothelium / drug effects
Urothelium / metabolism*
Urothelium / microbiology
rab GTP-Binding Proteins
rab27 GTP-Binding Proteins / genetics
rab27 GTP-Binding Proteins / metabolism*

Substances

Anti-Inflammatory Agents
KEAP1 protein, human
Keap1 protein, mouse
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
NFE2L2 protein, human
Nfe2l2 protein, mouse
Reactive Oxygen Species
rab27 GTP-Binding Proteins
Rab27b protein, mouse
Rab27B protein, human
rab GTP-Binding Proteins
Dimethyl Fumarate

Abstract

Publication types

MeSH terms

Substances

Grants and funding