Estrogen receptor alpha differentially modulates host immunity in the bladder and kidney in response to urinary tract...

The protective role of endogenous estrogen against Urinary Tract Infection (UTI) is well recognized, but the involvement of estrogen receptors (ERs) in modulating immunity in the urinary tract during UTI pathogenesis has not been investigated. The current study investigates the role of ERα in modulating immune responses and UTI outcome. Mice were pre-treated with either ERα agonist, propyl-pyrazole-triol (PPT), or ERα antagonist, methyl-piperidino-pyrazole (MPP), before experimental UTI. The UTI outcome was determined by checking the bacterial load, CD55 and TNFα expression in the bladder and kidney tissues. We observed opposite effects of PPT and MPP treatment on bacterial clearance in bladder versus kidney. PPT significantly reduced bacterial load (P < 0.05) only in the kidney, with minimal changes in CD55 and TNFα levels. In contrast, MPP showed remarkable bacterial clearance only in the bladder that corresponded with reduced CD55 and TNFα expression. MPP treatment in uninfected state induced a significant increase in TNFα production (P < 0.05) in the bladder, but not in the kidney. Our results suggest a protective role of ERα in the kidney. However, protection in the bladder may be mediated via other ER subtypes that may be involved in boosting the local immune responses. Drugs targeting specific ERs in bladder may serve as an adjunct treatment for boosting immune responses in the urogenital tract for efficient bacterial clearance.