Estrogen Receptor-Alpha (ESR1) Governs the Lower Female Reproductive Tract Vulnerability to Candida albicans.

Laura Salinas-Muñoz,Jennifer C Brazil,Carlota Fernández-Pacheco,Enrique Mercader,Paloma Sánchez-Mateos,Raúl Campos-Fernández,Andrés Hidalgo,Fernando Asensio,Lara Matilla,Maria A Muñoz-Fernández,Irene Olivera-Valle,Julio García-Bordas,Miguel Relloso,Rafael Samaniego,Charles A Parkos

doi:10.3389/fimmu.2018.01033

Abstract

Estradiol-based therapies predispose women to vaginal infections. Moreover, it has long been known that neutrophils are absent from the vaginal lumen during the ovulatory phase (high estradiol). However, the mechanisms that regulate neutrophil influx to the vagina remain unknown. We investigated the neutrophil transepithelial migration (TEM) into the vaginal lumen. We revealed that estradiol reduces the CD44 and CD47 epithelial expression in the vaginal ectocervix and fornix, which retain neutrophils at the apical epithelium through the estradiol receptor-alpha. In contrast, luteal progesterone increases epithelial expression of CD44 and CD47 to promote neutrophil migration into the vaginal lumen and Candida albicans destruction. Distinctive to vaginal mucosa, neutrophil infiltration is contingent to sex hormones to prevent sperm from neutrophil attack; although it may compromise immunity during ovulation. Thus, sex hormones orchestrate tolerance and immunity in the vaginal lumen by regulating neutrophil TEM.

Highlights

Neutrophils maintain mucosal immunity since they are very efficient at phagocytosing and killing invading microbes [1]
We discovered that E2-treatment, through the estradiol receptoralpha (ESR1), induces epithelial downregulation of CD47 and CD44, and retains neutrophils at the mucosa
To study the role of sex hormones in neutrophil influx into the vaginal lumen, we set up a model of C. albicans vaginal infection in hormone-treated mice

Summary

Introduction

Neutrophils maintain mucosal immunity since they are very efficient at phagocytosing and killing invading microbes [1]. Neutrophils develop in the bone marrow [1] until they are mature to circulate in the blood [3]. Resident sentinel cells release proinflammatory mediators and chemoattractants that activate and guide neutrophils through the interstitium toward sites of infection/inflammation [5,6,7]. In mucosal tissues, such as bladder, lung, and gut, epithelial cells produce chemoattractants that guide neutrophils through the interstitium until they reach the subepithelial space [8].

Objectives

Results

Conclusion