Abstract
Objective This study investigated the alterations in macrophage polarization in patients with endometriosis as well as the underlying molecular mechanisms. Methods Peritoneal washings, serum samples, and endometrial tissues were collected from endometriosis patients and control subjects. Endometrial stromal cells (ESCs) were isolated from endometrial tissue, and conditioned medium was prepared by treating ESCs with or without various concentrations of interleukin- (IL-) 6, estrogen, or progestin. The frequencies of CD86+ and CD163+ cells and expression levels of these markers as well as the cytokines IL-12 and IL-10 were measured in THP-1- (human monocytic leukemia cell) derived macrophages. Results There was a decrease in the percentage of CD86+ macrophages in the peritoneal wash solution of patients with endometriosis. Ectopic endometrial homogenates could promote M1 to M2 macrophage polarization in response to lipopolysaccharide (LPS), as evidenced by the increased percentage of CD163+ macrophages and increased IL-10 expression as well as a decreased percentage of CD86+ cells and lower IL-12 expression. In contrast, addition of serum from women with endometriosis to THP-1 cells resulted in the polarization of macrophages towards both M1 and M2 phenotypes. Upregulation of Smad2/Smad3 in macrophages upon exposure to eutopic and ectopic endometrial homogenates as well as serum of women with endometriosis was observed, and blockage of Smad2/Smad3 with their inhibitor SB431542 could reverse the macrophage polarization from M1 to M2. Conditioned medium induced by IL-6, but neither estrogen nor progestin, could facilitate M2 polarization. Neutralization of IL-6 diminished macrophage M2 polarization in endometriosis. Conclusion This study provides detailed evidence supporting alterations in M1 to M2 macrophage polarization that may contribute to the initiation as well as progression of endometriosis.
Highlights
Endometriosis is a common nonmalignant gynecological disorder affecting 10–15% of women of reproductive age that manifests with the presence of ectopic endometrial cells and stroma in various locations outside of the uterine cavity, mainly in the peritoneal cavity [1]
There were no significant differences in the percentages of HLA-DR+ or CD163+ macrophages between control participants and endometriosis patients
The ratio of CD163+/CD86+ macrophages was elevated in endometriosis patients, especially in patients with advanced endometriosis, who had a significantly higher ratio of CD163+/CD86+ macrophages than those with stage I-II endometriosis
Summary
Endometriosis is a common nonmalignant gynecological disorder affecting 10–15% of women of reproductive age that manifests with the presence of ectopic endometrial cells and stroma in various locations outside of the uterine cavity, mainly in the peritoneal cavity [1]. A convincing hypothesis for the etiology of endometriosis has been that endometrial debris is refluxed by retrograde menstruation implant into the abdominal cavity where it grows and induces chronic inflammation with formation of adhesions. During this process, alterations in multiple aspects of humoral and cell-mediated immunity contribute to the pathogenesis of endometriosis [3,4,5]. Local and systemic immune factors, cytokines, and growth factors that are secreted by either immune or endometrial cells may favor the ectopic implantation and growth
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