Glucocorticoids Facilitate Uterine Receptivity through Regulating the Immune Response

Presentation Number: MON 374
Date of Presentation: April 3rd, 2017

Shannon D. Whirledge*1 and John A Cidlowski2
1Yale School of Medicine, New Haven, CT, 2NIEHS/NIH, Research Triangle Park, NC


Endometrial receptivity is a key factor for successful implantation, and the immune system plays a deciding role in establishing receptivity. Prior to implantation and during early pregnancy, dynamic changes occur in the local immune system of the female reproductive tract that promote reproductive success, including the induction of pro-inflammatory cytokines and invasion of activated immune cells. Disruption to this delicate immune balance can decrease uterine receptivity and cause implantation failure. Glucocorticoids are primary stress hormones that function to maintain immune homeostasis. We have recently discovered that GR signaling within the uterus is critical to establishing uterine receptivity and implantation. To define the role of glucocorticoid signaling in the uterine immune response during early pregnancy, we evaluated the expression of immunomodulatory genes and cytokines and assessed immune cell trafficking in the uterus of control and uterine-specific GR knockout mice. In control mice, gene expression analysis by nanostring technology determined that immunology-related genes demonstrate precise timing of expression. Prior to implantation, 168 genes were induced or repressed in the uterus compared to a non-pregnant mouse. At implantation, a unique cohort of 191 immunology-related genes became regulated and genes that had been previously up-regulated became repressed. Uterine cytokine expression also demonstrated a temporal pattern of regulation. Conversely, mice lacking GR in the uterus demonstrated dysregulated gene and cytokine expression. Prior to implantation and during implantation many immunology-related genes were no longer regulated in the uterus of uterine GR knockout mice, suggesting that uterine GR maintains the expression of these genes. Moreover, unique immunology-related genes were induced and repressed during early pregnancy in the uterine GR knockout mice compared to controls. Dysregulation of genes and cytokines essential to the immune response corresponded to altered immune cell trafficking. Macrophage recruitment, required for embryo implantation, was impaired in the uterine GR knockout mice. Regulatory T-cells and neutrophils demonstrated increased recruitment in the uterine GR knockout mice compared to controls. These data indicate that glucocorticoid signaling in the uterus acts a key regulator of the immune response and is required to promote an appropriate immune cell balance.


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