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

• Published in: Endocrinology (Philadelphia) Vol. 159; no. 1; pp. 103 - 118
• Main Authors: Burns, Katherine A, Thomas, Seddon Y, Hamilton, Katherine J, Young, Steven L, Cook, Donald N, Korach, Kenneth S
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.01.2018; Oxford University Press
• Subjects: 17β-Estradiol; Animals; Ascitic Fluid - immunology; Ascitic Fluid - metabolism; Ascitic Fluid - pathology; Biomarkers - metabolism; Crosstalk; Dependence; Disease Progression; Endocrinology; Endometriosis; Endometriosis - immunology; Endometriosis - metabolism; Endometriosis - pathology; Endometriosis - physiopathology; Endometrium - immunology; Endometrium - metabolism; Endometrium - pathology; Endometrium - physiopathology; Estradiol - administration & dosage; Estradiol - metabolism; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Females; Gene expression; Gene Expression Regulation; Gynecological diseases; Immune system; Immunity, Innate; Infiltration; Innate immunity; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukins; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Lesions; Leukocytes (neutrophilic); Macrophage Activation; Macrophages; Menopause; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Ovariectomy; Peritoneal fluid; Peritoneum; Random Allocation; Sex hormones; Signal Transduction; Signaling; Uterus
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2017-00562

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 (E2) and estrogen receptor (ER) α within 72 hours of disease initiation. Using wild-type and ERα 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 E2/ERα plays a minor role in early lesion development. Immune-mediated signaling predominates E2-mediated signaling, but 48 hours after the initiation of disease, a blunted interleukin (IL)-6-mediated response is found in developing lesions lacking ERα. Our data provide evidence that the early initiation of endometriosis is predominantly dependent on the immune system, whereas E2/ERα/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. 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.