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Abstract: SA-OR047

IL-6/Stat3 Signaling Promotes Antimicrobial Peptide Expression and Limits Epithelial Invasion and Ascending Infection by Uropathogenic Escherichia coli

Session Information

Category: Developmental Biology and Inherited Kidney Diseases

  • 403 Pediatric Nephrology

Authors

  • Gupta, Sudipti, Nationwide Children's Hospital , Columbus, Ohio, United States
  • Ching, Christina B., Nationwide Children''s Hospital, Columbus, Ohio, United States
  • Li, Birong, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Cortado, Hanna H., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States
  • McHugh, Kirk M., Ohio State University, Columbus, Ohio, United States
  • Becknell, Brian, Ohio State University, Columbus, Ohio, United States
Background

The signaling networks regulating host antimicrobial activity during UTI are incompletely understood. Bacterial virulence varies inversely with IL-6 production during UTI, suggesting IL-6 signaling plays an important role in bacterial containment in infection. The specific contributions of IL-6 to host immunity against uropathogens, however, are unknown. We hypothesized that IL-6 activates the Stat3 transcription factor in infected urothelium, driving an antimicrobial program of gene expression with consequences on bacterial colonization of the urinary tract.

Methods

C57BL/6J, IL-6 deficient, or Stat3 conditional knockout mice were transurethrally inoculated with uropathogenic E. coli (UPEC). IL-6 production, Stat3 phosphorylation (pStat3), and antimicrobial peptide (AMP) mRNA expression were analyzed by ELISA, Western blotting, and qRT-PCR, respectively. Intracellular bacterial communities (IBC) were enumerated by beta-galactosidase staining. Bacterial invasion assays were performed in IL-6 or carrier treated human urothelial cells. The role of Tlr4 signaling in IL-6 signaling was established using C3H/HeJ mice (Lps-hyporesponsive) and C3H/HeOuJ (Lps-sensitive) controls. Chronic IL-6 depletion was evaluated by systemic administration of IL-6 neutralizing or isotype control antibody.

Results

Transurethral inoculation of UPEC leads to IL-6 secretion, urothelial pStat3, and activation of AMP transcription, in a Tlr4-dependent manner. Recombinant IL-6 elicits pStat3 and suppresses UPEC invasion in human urothelial cells. Systemic IL-6 administration promotes urothelial pStat3 and AMP expression in vivo. IL-6 deficiency leads to decreased urothelial pStat3 and AMP mRNA expression following UTI, accompanied by increased IBC formation and persistent bacteriuria. Moreover, chronic IL-6 depletion leads to increased renal bacterial burden and severe pyelonephritis in C3H/HeOuJ mice. Conditional Stat3 deletion results in reduced AMP mRNA levels and increased IBC formation following experimental UTI.

Conclusion

IL-6/Stat3 signaling drives a transcriptional program of antimicrobial gene expression in infected urothelium, with key roles in limiting epithelial invasion and ascending infection.

Funding

  • NIDDK Support