New Mechanism Identified in Urinary Tract Infection Host Defense

IL-6 promotes urothelial expulsion of intracellular bacteria, limiting recurrence risk.

A recent study published in the Journal of Innate Immunity provides new insights into how the body actively defends against urinary tract infections (UTIs). Led by Christina B. Ching, MD, principal investigator of the Ching Lab in the Abigail Wexner Research Institute and director of Translational Research in Pediatric Urology at Nationwide Children’s Hospital, the research demonstrates that the cytokine interleukin-6 (IL-6) promotes the expulsion of intracellular uropathogenic Escherichia coli (UPEC) from urothelial cells. This expulsion limits the formation of intracellular bacterial communities (IBCs), a critical step in the development of recurrent infection.

“While past research showed IL-6 plays a role in infection resistance, these findings are particularly exciting because we uncovered a previously unknown mechanism by which IL-6 actually helps flush bacteria out of the bladder,” says Dr. Ching.

UTIs remain a common and clinically significant condition in pediatric populations, with the potential for recurrent infection, kidney damage and long-term morbidity. A key challenge in management is UPEC’s ability to invade urothelial cells and form IBCs, which protect bacteria from both host immune responses and antibiotic therapy.

“Bacteria can hide within the lining of the urinary tract, making infections harder to clear and more likely to recur,” explains Dr. Ching. “We wanted to understand what mechanisms the body uses to prevent that from happening.”

Investigators used both in vivo mouse models and in vitro human urothelial cell systems to examine the role of IL-6 during early infection. Mice that lacked IL-6 or received neutralizing antibodies developed much higher intracellular bacterial burdens and formed more IBCs than controls. In contrast, administering recombinant IL-6 restored bacterial clearance and reduced IBC formation.

In human cells, IL-6 did not affect bacterial attachment or invasion. Instead, it enhanced the expulsion of intracellular bacteria back into the bladder lumen.

“What we saw was that IL-6 was not just activating inflammation, a known role for IL-6,” says Dr. Ching, who is also a clinical assistant professor of Urology at The Ohio State University. “It was also directly helping bladder cells push bacteria out before they can establish protected communities. This is a novel finding for IL-6.”

These insights refine the understanding of IL-6 in UTI pathogenesis. While IL-6 is known as a pro-inflammatory cytokine, studies have not previously explored its direct effect on epithelial cell function in the urinary tract. By promoting early bacterial expulsion, IL-6 disrupts a key step in UPEC survival.

“When bacteria remain inside cells, they are shielded from antibiotics and normal urinary flow,” Dr. Ching notes. “By moving them back into the bladder, IL-6 makes them more vulnerable to clearance.”

The study also raises important clinical questions regarding variability in patient susceptibility to infection. Differences in IL-6 signaling, whether due to genetic factors, medication effects or bacterial immune evasion strategies, may contribute to recurrent or severe infections.

“We think IL-6 response may be one factor that helps explain why some patients are more prone to UTIs than others,” Dr. Ching says.

Although these findings are based on early infection models, they suggest potential translational applications. Future research will evaluate IL-6 pathways in human biospecimens and assess whether IL-6 profiles could support risk stratification or predict infection susceptibility.

“This is an early step,” Dr. Ching emphasizes. “Understanding how IL-6 works will help identify downstream pathways that could be targeted therapeutically.”

Reference:

Gupta S, Rajak S, Cortado H, Becknell B, Spencer JD, Ching CB. Interleukin-6 Limits Host Susceptibility to Urinary Tract Infection by Promoting Urothelial Expulsion of Intracellular Bacteria. J Innate Immun. 2026;18(1):120-125. doi:10.1159/000550787.

Image Credit: Nationwide Children’s