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.

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