Understanding the role of neutrophils in female reproductive tract (FRT) epithelial barrier remodeling in vivo
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Date
2019-05-27
Authors
Yazdanpanah, Atta
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Abstract
When the mucous membrane of the female reproductive tract (FRT) is compromised, women are more susceptible to pathogens, especially human immunodeficiency virus (HIV), which emphasizes the importance of an intact barrier in female vaginal health. In a large human cohort analysis, previous studies have observed a strong association between neutrophil activation, epithelial barrier damage and HIV infection, supporting the hypothesis that these innate cells are an important modulator of the vaginal mucosal barrier and HIV susceptibility. However, a gap in knowledge is the biological mechanisms that regulate the recruitment of neutrophils and their interaction with the vaginal epithelium. Here, we show, using a mouse model, that neutrophils are recruited into the vaginal mucosa in response to progesterone. Proteomic analysis of the cervicovaginal lavage fluid revealed that pathways involved in epithelial barrier disruption were activated, and that these pathways were significantly reduced after in vivo depletion of neutrophils. We show that vaginal neutrophils expressed high levels of CXCR2 that allowed their positioning along the outer layers of the vaginal epithelium. Vaginal inoculation of BSA at steady-state and neutrophil depletion did not assign neutrophils to epithelial disruption. Furthermore, elevated expression of neutrophil-associated mediators MPO, MMP8 and elastase in the diestrus phase were observed. In the presence of anaerobic bacteria that are associated with bacterial vaginosis (BV), expression of neutrophil elastase, MMP8, and MMP9 trended higher, suggesting that different bacteria species can elevate inflammation reactions by activating mucosal neutrophils. These data argue that the mouse model can recapitulate key aspects of neutrophil:epithelium interactions in vivo. Our overall goal is to further define the role of mucosal neutrophils, and whether blocking their recruitment/activation can reduce HIV susceptibility.
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Keywords
Female reproductive tract (FRT), Neutrophils, Cervicovaginal lavage, Bacterial vaginosis (BV), HIV susceptibility