The role of monocytes in the maintenance of ovarian follicle health
Creators: name: Younesi, Simin
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 321503
subject: Reproduction
subject: FOS: Medical biotechnology

description: Monocytes and macrophages are the primary responders to systemic immune challenges which induce the release of cytokines and other inflammatory mediators that regulate a wide range of physiological processes. Previous research has demonstrated that monocytes and macrophages are the most abundant innate immune cell populations in the ovary, where they play a critical role in ovarian follicle maturation in preparation for ovulation, corpus luteum formation and regression. However, the functional role of ovarian monocytes and macrophages in supporting the maturing follicle from the primordial through to the later stages is unknown. Here, we utilised a Cx3cr1-Dtr transgenic Wistar rat model that allows a conditional depletion of monocytes to investigate the role of these major innate immune cell populations in ovarian follicle health. By using this model, we first examined the influence of immune cell manipulation on several indices of ovarian health in sexually-mature adult rats. We also investigated the vulnerability of the adult ovary to an immune challenge and whether an acute disruption to the ovarian milieu, induced by acute depletion of monocytes, would exacerbate ovarian responses to a subsequent immune challenge. Since an appropriate functioning of the immune system is important for reproductive development and early life immune challenges have been shown to disrupt female reproductive function later in life, we also utilised a Cx3cr1-Dtr rat model to investigate the impact of a conditional depletion of monocytes in the neonatal period on adult ovarian health. 

Our findings show that circulating monocyte depletion leads to a significant reduction in ovarian monocytes and macrophages populations. However, these robust changes had minimal effects on ovarian follicle health both acutely and long-term, with no changes in the numbers of different follicle populations, ovarian apoptosis or corpus luteum development and regression, despite acute reduction in circulating levels of anti-Müllerian hormone (AMH), a marker of an ovarian reserve. These data reveal that the healthy adult ovary is remarkably resistant to perturbations of circulating and ovarian monocytes. However, we have shown that monocyte perturbation decreased circulating luteinising hormone (LH) levels and have also increased the vulnerability of the ovary to a subsequent immune challenge, indicating a transient suppression of ovulatory capacity that is likely to be restored upon the resolution of the pro-inflammatory environment. Our neonatal studies have revealed that a transient depletion of monocytes during the second, but not third week of life, induced a long-term reduction in circulating LH, similar to our findings in adult rats.  These changes corresponded with a reduced ovarian gene expression of gonadotropin receptors and a reduction in the number of primary and antral follicles, compared to untreated controls. However, there were no alterations in the quantity of ovulatory follicles or the presence of corpus luteum, indicating an encouraging potential for overall reproductive success despite an immune perturbation early in life.

These data indicate an important role of monocytes in the development of the ovary and long-term ovarian health, as well as in mediating the effects of a systemic immune challenge on ovarian function. Importantly, the findings reported in this dissertation indicate that although acute changes to the ovarian immune milieu can disrupt several indices of reproductive function, these are unlikely to affect fertility and pregnancy success.