Serum and Ectopic Endometrium from Women with Endometriosis Modulate Macrophage M1/M2 Polarization via the Smad2/Smad3 Pathway

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.

The Role of Myeloid-Derived Suppressor Cells (MDSCs) in the Development and/or Progression of Endometriosis-State of the Art

“…Interestingly, there was an upward trend in the percentage of the M2 population from stage I to IV and a reverse trend in the case of the M1 cell phenotype. These findings agree with other reports on the importance of the M1 to M2 switch both in mouse models and in endometriosis in humans [ 39 ]. Other reports based on a mouse model of endometriosis indicate the importance of endogenous macrophages in tissue remodeling in the process of endometriosis development and the necessity of the M1/M2 phenotype switch to growth in the ectopic lesion [ 40 ].…”

Biomarkers for the Noninvasive Diagnosis of Endometriosis: State of the Art and Future Perspectives

“…Elevated levels of this cytokine-induced a decreased activity of cytotoxic T lymphocytes and CD+ helper cells into the peritoneal fluid of affected patients [46]. Furthermore, M1 to M2 macrophage polarization is promoted by the increased expression of IL-10 [47].…”

The Role of Macrophages in Oocyte Donation Pregnancy: A Systematic Review

“…At the same time, the number of M2 was decreased in all phases, suggesting that the trend of macrophages polarizing to M1 might contribute to the cause of endometriosis [40]. However, a more recent study found that the eutopic endometrial homogenate from patients with endometriosis has the ability to differentiate macrophages from M1 to M2 [41]. This study also showed that M1 decreased in peritoneal washes from endometriosis patients, especially at a later stage of the disease (III and IV).…”