Ureaplasma Urealyticum Infection Contributes to the Development of Pelvic Endometriosis Through Toll-Like Receptor 2

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.

Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review

“…Despite the prevalence of and disablement caused by endometriosis, its pathogenesis remains unknown (100). A lesser known and under-investigated hypothesis proposes that microbes may contribute to endometriosis etiopathology (i.e., "bacterial contamination hypothesis") (101) via an inflammatory response and TLR4 (102-104) and TLR2 activation (104,105). This research is notable in the context of studies on pathogen persistence and pathobionts in infection-associated chronic illnesses and how they may be implicated in multiple pathologies (106-108).…”

Ureaplasma urealyticum induces polymorphonuclear elastase to change semen properties and reduce sperm motility: a prospective observational study

“… 28 UU might activate the immune response in vivo and enhance the chemotaxis and stress effects of inflammatory cells such as neutrophils. 29 For reasons of high cost and low patient compliance and acceptance, we did not investigate sperm DNA fragmentation. This is a major limitation of our study, and we plan to include such an investigation in our future in-depth analysis.…”

Droplet digital PCR (ddPCR) for the detection and quantification of Ureaplasma spp.

“…In addition, several in vitro studis have demonstrated that Ureaplasma spp. modulate cytokine [34,35] and proinflammatory responses in a dose-dependent manner [36]. Interestingly, one study indicated that a high load of U. parvum (10 7 CFU/ml) can significantly increase prothrombin/thrombin mRNA expression to promote the onset of PPROM but that a lower load (10 5 CFU/ml) had no significant effect [6].…”