Endometriotic Peritoneal Fluid Stimulates Recruitment of CD4+CD25highFOXP3+ Treg Cells.

Joanna Olkowska-Truchanowicz,Izabela Janiuk,Alicja Sztokfisz-Ignasiak,Filip Dąbrowski,Aneta Zwierzchowska,Katarzyna Bocian,Jacek Malejczyk,Ewa Barcz,Grażyna Korczak-Kowalska

doi:10.3390/jcm10173789

Abstract

Endometriosis is a common gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus. The disease is associated with disturbed local and systemic immunity. It has been reported that the proportion of CD4+CD25highFOXP3+ Treg cells may be significantly increased in the peritoneal fluid of patients with endometriosis. Therefore, the aim of our study was to investigate whether the proportions of Treg cells in the peritoneal cavity of patients with endometriosis are related to the chemotactic and stimulatory activity of the local peritoneal milieu. The peritoneal fluid was collected from 13 women with ovarian endometriosis and 12 control women without the disease. T cell populations were analyzed by flow cytometry, cytokines and chemokines were evaluated using the cytometric bead kit, and cell chemotaxis was studied by cell migration assay. We confirmed that the proportions of Treg cells are increased in the peritoneal fluid of women with endometriosis as compared to the control women. Endometriosis was also associated with elevated concentrations of IL-6, IL-10, and TGF-β1/2 as well as CCL20, CXCL8, CXCL9, and CXCL10. We did not reveal any changes in the proportion of peritoneal Th17 cells and concentrations of IL-17A. Peritoneal Treg cells positively correlated with concentrations of TGF-β, IL-10, and CCL20. Endometriotic peritoneal fluid stimulated chemotaxis of both CD4+ and Treg cells. This chemotactic activity positively correlated with concentrations of CCL20. CCL20 stimulated the migration of Treg cells, and the chemotactic activity of the endometriotic peritoneal fluid was inhibited by neutralizing anti-CCL20 antibodies. These results imply that increased proportions of the peritoneal Treg cells in women with endometriosis may result from attraction and activation by local chemokines and cytokines, especially CCL20 and TGF-β. Since Treg cells contribute to the immunopathogenesis of endometriosis, their chemotaxis and activation may be considered as a target for therapeutic intervention.

Highlights

Endometriosis is a common estrogen-dependent gynecological disorder that arises due to the presence of endometrial-like tissue located outside the uterine cavity, mainly on the pelvic viscera and/or ovaries [1,2,3]
We found that the proportions of both CD25lowFOXP3+ and CD25highFOXP3+ cells (Treg cells) within the CD4+ T cell population were significantly elevated in the peritoneal fluid from the endometriosis group as compared to healthy women (Figure 1E,F)
It has been reported that endometriosis is associated with increased proportions of the peritoneal Treg cells that may play a role in the immunopathogenesis of this disorder [26,27,29,31,34,35]

Summary

Introduction

Endometriosis is a common estrogen-dependent gynecological disorder that arises due to the presence of endometrial-like tissue (endometrial glands and stroma) located outside the uterine cavity, mainly on the pelvic viscera and/or ovaries [1,2,3]. Endometriosis affects about 10% of women in their reproductive age It has a significant impact on patients’ life quality and constitutes a significant clinical and social problem. It is generally accepted that ectopic endometriotic lesions may develop from the endometrial cells shed during menstruation, which get into the peritoneal cavity in the course of a retrograde menstruation [2]. The mechanisms that facilitate survival and ectopic implantation and growth of endometrial cells are largely unknown. These phenomena may be at least partially explained by abrogated local estrogen production and progesterone resistance [9,10,11], as well as the resistance of endometriotic cells to apoptosis and their increased adhesiveness and invasiveness [2,12]. It is possible that the survival of endometriotic cells is due to their impaired elimination by the cells of the local immune system, e.g., NK cells and macrophages [13]

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