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

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.