Early Endometriosis in Females Is Directed by Immune-Mediated Estrogen Receptor α and IL-6 Cross-Talk

Abstract

Endometriosis is a gynecological disease that negatively affects the health of 1 in 10 women. Although more information is known about late stage disease, the early initiation of endometriosis and lesion development is poorly understood. Herein, we use a uterine tissue transfer mouse model of endometriosis to examine early disease development and its dependence on estradiol (E ₂) and estrogen receptor (ER) α within 72 hours of disease initiation. Using wild-type and ER α knockout mice as hosts or donors, we find substantial infiltration of neutrophils and macrophages into the peritoneal cavity. Examining cell infiltration, lesion gene expression, and peritoneal fluid, we find that E ₂/ER α plays a minor role in early lesion development. Immune-mediated signaling predominates E ₂-mediated signaling, but 48 hours after the initiation of disease, a blunted interleukin (IL)-6-mediated response is found in developing lesions lacking ER α. Our data provide evidence that the early initiation of endometriosis is predominantly dependent on the immune system, whereas E ₂/ER α/IL-6-mediated cross-talk plays a partial role. These findings suggest there are two phases of endometriosis—an immune-dependent phase and a hormone-dependent phase, and that targeting the innate immune system could prevent lesion attachment in this susceptible population of women.

Abstract

A mouse model of endometriosis, used to examine the early initiation of disease, revealed that two phases of disease exist—an immune-predominant phase and hormone-predominant phase.