Estrogen Action in the Epithelial Cells of the Mouse Vagina Regulates Neutrophil Infiltration and Vaginal Tissue Integrity

Abstract

In the female reproductive tract, the innate immune system is modulated by two sex steroid hormones, estrogen and progesterone. A cyclical wave of neutrophils in the vaginal lumen is triggered by chemokines and correlates with circulating estrogen levels. Classical estrogen signaling in the female reproductive tract is activated through estrogen receptor α (encoded by the Esr1 gene). To study the role of estrogen action in the vagina, we used a mouse model in which Esr1 was conditionally ablated from the epithelial cells (Wnt7acre/+; Esr1f/f). Histological evidence showed that in response to a physical stress, the lack of ESR1 caused the vaginal epithelium to deteriorate due to the absence of a protective cornified layer and a reduction in keratin production. In the absence of ESR1 in the vaginal epithelial tissue, we also observed an excess of neutrophil infiltration, regardless of the estrous cycle stage. The histological presence of neutrophils was found to correlate with persistent enzymatic activity in the cervical-vaginal fluid. Together, these findings suggest that ESR1 activity in the vaginal epithelial cells is required to maintain proper structural integrity of the vagina and immune response, both of which are necessary for protecting the vagina against physical damage and resetting the vaginal environment.

The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines

“…These PMN exhibited enhanced expression of MMP9, the enzyme required for transepithelial migration. ESR1ablated mice also exhibited reduced levels of bacterial infiltration compared to wild-type animals [29].…”

“…ESR1ablated mice also exhibited reduced levels of bacterial infiltration compared to wild-type animals [29]. These PMN exhibited enhanced expression of MMP9, the enzyme required for transepithelial migration.…”

“…These data were underscored by a further recent study documenting the importance of E2 in maintaining the integrity of the vaginal epithelium and regulating PMN flux across this cell barrier [29]. In this study, the oestrogen receptor (ESR1) was conditionally ablated in the murine vaginal epithelium.…”

“…The process whereby circulatory PMN migrate to sites of infection in the female reproductive tract is currently unclear, but it would appear that cyclical steroid sex hormones levels play an important role in this process [20,[28][29][30][31]. Several years ago Tibbetts et al .…”

“…In such animals, the lack of an oestrogen response was determined to render the vaginal tissue highly susceptible to laceration during mating. This was determined to result from diminished keratin expression and lack of a cornified protective layer [29].…”