Estrogen receptors in human bladder cells regulate innate cytokine responses to differentially modulate uropathogenic E. coli colonization.
2020; 226 (1): 152020
Estrogen receptor alpha differentially modulates host immunity in the bladder and kidney in response to urinary tract infection
AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY
2019; 7 (3): 110?22
The bladder epithelial cells elicit robust innate immune responses against urinary tract infections (UTIs) for preventing the bacterial colonization. Physiological fluctuations in circulating estrogen levels in women increase the susceptibility to UTI pathogenesis, often resulting in adverse health outcomes. Dr adhesin bearing Escherichia coli (Dr E. coli) cause recurrent UTIs in menopausal women and acute pyelonephritis in pregnant women. Dr E. coli bind to epithelial cells via host innate immune receptor CD55, under hormonal influence. The role of estrogens or estrogen receptors (ERs) in regulating the innate immune responses in the bladder are poorly understood. In the current study, we investigated the role of ER?, ER? and GPR30 in modulating the innate immune responses against Dr E. coli induced UTI using human bladder epithelial carcinoma 5637 cells (HBEC). Both ER? and ER? agonist treatment in bladder cells induced a protection against Dr E. coli invasion via upregulation of TNF? and downregulation of CD55 and IL10, and these effects were reversed by action of ER? and ER? antagoinsts. In contrast, the agonist-mediated activation of GPR30 led to an increased bacterial colonization due to suppression of innate immune factors in the bladder cells, and these effects were reversed by the antagonist-mediated suppression of GPR30. Further, siRNA-mediated ER? knockdown in the bladder cells reversed the protection against bacterial invasion observed in the ER? positive bladder cells, by modulating the gene expression of TNF?, CD55 and IL10, thus confirming the protective role of ER?. We demonstrate for the first time a protective role of nuclear ERs, ER? and ER? but not of membrane ER, GPR30 against Dr E. coli invasion in HBEC 5637 cells. These findings have many clinical implications and suggest that ERs may serve as potential drug targets towards developing novel therapeutics for regulating local innate immunity and treating UTIs.
View details for DOI 10.1016/j.imbio.2020.152020
View details for PubMedID 33246308
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 ER? in modulating immune responses and UTI outcome. Mice were pre-treated with either ER? agonist, propyl-pyrazole-triol (PPT), or ER? antagonist, methyl-piperidino-pyrazole (MPP), before experimental UTI. The UTI outcome was determined by checking the bacterial load, CD55 and TNF? 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 TNF? levels. In contrast, MPP showed remarkable bacterial clearance only in the bladder that corresponded with reduced CD55 and TNF? expression. MPP treatment in uninfected state induced a significant increase in TNF? production (P < 0.05) in the bladder, but not in the kidney. Our results suggest a protective role of ER? 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.
View details for Web of Science ID 000473314700002
View details for PubMedID 31317051
View details for PubMedCentralID PMC6627544