Transcription factor Stat3 may prevent experimental chronic urinary tract infection through an impact on urothelial regeneration and AMP induction
Sudipti Gupta, PhD, Evan Alexander, BS, Hanna Cortado, BS, Brian Becknell, MD PhD, John D. Spencer, MD, Christina B. Ching, MD.
Nationwide Children's Hospital - Kidney Urinary Tract Center, Columbus, OH, USA.
Background: Chronic urinary tract infections (UTIs) cause significant morbidity with our understanding of their pathogenesis being poor. This limits our ability to predict those at risk and prevent them from occurring. We have previously identified IL-6 as an important cytokine involved in UTI susceptibility, demonstrating increased UPEC susceptibility acutely if lost in a transgenic mouse model of UTI. IL-6 signals through the downstream transcription factor, Stat3. We sought to identify what role Stat3 specifically may play in UTI susceptibility, particularly in chronic infection. We hypothesized that Stat3 is involved in limiting UTI development and chronicity. Methods: Experimental UPEC UTI was induced in 6-8 weeks old female mice, including an FVB/N wild type control (WT) and a transgenic mouse expressing constitutively active Stat3 (Stat3C). Bladder and urine bacterial burden were evaluated at time points up to 7 days post infection (dpi); and IBCs enumerated. Histopathologic evaluation was performed via H&E and immunofluorescent (IF) staining. qRT-PCR was used for quantification of antimicrobial peptide (AMP) expression. Results were evaluated by Mann-Whitney U test with p<0.05 being significant. Results: Compared to WT, Stat3C mice demonstrated significantly decreased urine bacterial burden at 24 hours post infection (hpi) and 7dpi with bladder burden being significantly less at 7dpi. IBC phenotype at 6 hpi was not significantly different between mice. H&E of Stat3C bladders at 24hpi showed less inflammation and edema compared to WT. Both uninfected and infected Stat3C urothelium showed Stat3 reactivity by IF with relatively little staining in WT mice. Stat3C and WT urothelium demonstrated induction of pStat3 after infection with apparent persistence of pSTAT3 in Stat3C at 7dpi. Stat3C urothelium showed more Ki67 staining at 24hpi compared to WT. There was significantly higher induction of certain AMPs after UTI in Stat3C vs. WT mice on qRT-PCR. Conclusions: Stat3 appears significant in protecting against chronic UTI. This could be through differences in urothelial regeneration and turn over as well as through elevated AMP expression. Understanding what pathways may be involved in UTI chronicity could be targeted to try and prevent such pathology.
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