Abstract
Endometriosis is a chronic gynecological disorder, characterized by the presence of ectopic endometrial tissue outside the uterine cavity. Among several hypotheses, Sampson's theory of retrograde menstruation is still applicable. Recent studies have reported the importance of inflammation among endometrial tissue, the peritoneum, and immune cells. However, less is known regarding the role of bacterial infection in the pathophysiology of endometriosis. We hypothesized that Ureaplasma urealyticum infection might contribute to the development of endometriosis by inducing the production of inflammatory mediators by peritoneal mesothelial cells (PMCs), possibly through TLR2. Hence, our objective was to reveal whether PMC infection by U. urealyticum is associated with endometriosis. Moreover, we aimed to demonstrate the molecular mechanism involved in this relationship. We developed a new infection-induced mouse model of endometriosis with wild type and Tlr2-deficient mice. Based on the in vivo mouse model, U. urealyticum-infected mice showed significantly increased numbers and sizes of ectopic endometriotic lesions. U. urealyticum upregulated not only the production of IL-6, CXCL1, and CCL2, but also the expression of ICAM-1, VCAM-1, and MMP2 in murine PMCs. Similarly, endometrial stromal cells dose-dependently produced IL-6, CXCL1, and CCL2 in response to U. urealyticum infection. The series of inflammatory responses in PMCs was mediated mainly through TLR2. The phosphorylation of ERK and JNK was observed when U. urealyticum was added to PMCs and knock out of Tlr2 inhibited these MAPKs phosphorylation. Based on our co-culture study, U. urealyticum-infected PMCs exhibited significantly increased attachment to ESCs compared with uninfected PMCs. Collectively, U. urealyticum infection promotes the development of endometriosis by increasing inflammatory mediators, adhesion molecules, and MMP-2 expression in PMCs through TLR2 signaling. Through our results, we present a theory that infection-induced pelvic inflammation contributes to the initiation and progression of endometriosis. Appropriate treatment of reproductive tract infection may decrease the prevalence of endometriosis.
Highlights
Endometriosis is a chronic gynecological disorder, characterized by the presence of ectopic endometrial tissue outside the uterine cavity; it affects 6–10% of women of reproductive age [1]
To verify the hypothesis that U. urealyticum infection in the peritoneal cavity is involved in the development of endometriosis, PMSG was injected into the peritoneal cavity of donor and recipient mice synchronized in their estrous cycles
More ectopic lesions developed in the group infected with U. urealyticum than in the uninfected group (P < 0.01), but there was no difference between infected WT and Tlr2-deficient mice (Figure 1C)
Summary
Endometriosis is a chronic gynecological disorder, characterized by the presence of ectopic endometrial tissue outside the uterine cavity; it affects 6–10% of women of reproductive age [1]. Sampson’s theory of retrograde menstruation is still applicable [2]. Some other theories such as alteration of response to estrogen and progesterone, endometrial stem cell implantation, Müllerian remnant abnormalities, and coelomic metaplasia have postulated [3, 4]. Recent studies have reported the importance of interactions among endometrial tissue, the peritoneum, and immune cells during development into endometriosis [5,6,7]. Tissue remodeling and repair, endometrial cell proliferation, angiogenesis, neurogenesis, and fibrosis are followed under the influence of regulatory T cells and T helper 2 cells [7,8,9,10]
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