Interleukin-6 Limits Host Susceptibility to Urinary Tract Infection by Promoting Urothelial Expulsion of Intracellular Bacteria.

Abstract

INTRODUCTION: Interleukin (IL)-6 has an important role in limiting urinary tract infection (UTI). Mice lacking IL-6 are more susceptible to uropathogenic Escherichia coli (UPEC), including increased formation of intracellular bacterial communities (IBCs). How IL-6 promotes UPEC clearance is unknown. We hypothesize IL-6 reduces UTI susceptibility by limiting IBC formation through an early mechanism of infection. METHODS: Female mice were treated with vehicle or neutralizing antibodies to inhibit IL-6 or the IL-6 receptor (IL-6R) prior to transurethral UPEC infection. In rescue experiments, murine recombinant (r)IL-6 was administered to IL-6 knockout (KO) mice. Bladder IBCs, urinary and bladder bacterial burden, and UPEC expulsion were quantified. For clinical translation, human urothelial cells were pretreated with human rIL-6 and infected with UPEC. Bacterial attachment, invasion, and expulsion were quantified. RESULTS: Neutralization of IL-6 or IL-6R increased bladder IBC counts compared to isotype controls. Similarly, while IL-6 KO mice exhibited higher IBC counts than wild-type controls, this phenotype was reversed by rIL-6 administration. Gentamicin protection assays confirmed increased intracellular UPEC burden and reduced bacterial expulsion in IL-6 KO bladders. rIL-6 treatment enhanced UPEC expulsion in human urothelial cells without impacting bacterial attachment or invasion. CONCLUSION: IL-6 facilitates UPEC expulsion, limiting intracellular UPEC early in infection and thus the initial formation of IBCs. Since IBC formation is a bottleneck in UPEC survival during UTI, these findings identify a mechanism whereby IL-6 reduces early UPEC urothelial infectivity.