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

• Published in: Cell reports (Cambridge) Vol. 37; no. 3; p. 109856
• Main Authors: Joshi, Chetanchandra S., Mora, Amy, Felder, Paul A., Mysorekar, Indira U.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.10.2021; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; ARE elements; autophagy; Bacterial Load; bladder; Cell Line, Tumor; dimethyl fumarate; Dimethyl Fumarate - pharmacology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - genetics; Escherichia coli Infections - metabolism; Escherichia coli Infections - microbiology; Female; HEK293 Cells; HMOX1; Host-Pathogen Interactions; Humans; KEAP1; 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; NQO1; Oxidative Stress; p62; rab GTP-Binding Proteins; rab27 GTP-Binding Proteins - genetics; rab27 GTP-Binding Proteins - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; UPEC; urinary tract infection; Urinary Tract Infections - drug therapy; Urinary Tract Infections - genetics; Urinary Tract Infections - metabolism; Urinary Tract Infections - microbiology; Uropathogenic Escherichia coli - pathogenicity; urothelium; Urothelium - drug effects; Urothelium - metabolism; Urothelium - microbiology; NQO1; autophagy; ARE elements; bladder; KEAP1; HMOX1; dimethyl fumarate; p62; urothelium; urinary tract infection; UPEC; oxidative stress
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109856

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. [Display omitted] •Urothelial cells produce reactive oxygen species upon uropathogenic E. coli infection•Infection results in dissociation of NRF2-KEAP1 complex and NRF2 nuclear translocation•NRF2 transcriptionally activates RAB27B and facilitates UPEC expulsion•Dimethyl fumarate, a NRF2 activator, promotes UPEC clearance and dampens inflammation Joshi et al. show that bladder epithelial cells activate the NRF2 pathway in response to urinary tract infections caused by uropathogenic E. coli (UPEC). The NRF2 pathway promotes UPEC expulsion, a major defense mechanism. Dimethyl fumarate, a NRF2 activator, promotes UPEC clearance in a mouse model of UTIs.