Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis

Abstract

Summary Alterations in estrogen-mediated cellular signaling play an essential role in the pathogenesis of endometriosis. In addition to higher estrogen receptor (ER)β levels, enhanced ERβ activity was detected in endometriotic tissues, and the inhibition of enhanced ERβ activity by an ERβ-selective antagonist suppressed mouse ectopic lesion growth. Notably, gain of ERβ function stimulated the progression of endometriosis. As a mechanism to evade endogenous immune surveillance for cell survival, ERβ interacts with cellular apoptotic machinery in the cytoplasm to inhibit TNFα-induced apoptosis. ERβ also interacts with components of the cytoplasmic inflammasome to increase interleukin-1β and thus enhance its cellular adhesion and proliferation properties. Furthermore, this gain of ERβ function enhances epithelial-mesenchymal transition signaling, thereby increasing the invasion activity of endometriotic tissues for establishment of ectopic lesions. Collectively, we reveal how endometrial tissue generated by retrograde menstruation can escape immune surveillance and develop into sustained ectopic lesions via gain of ERβ function.

Malignant peritoneal mesothelioma in patients with endometriosis

“…The mechanism by which chronic serosal inflammation induces MM is not yet fully understood, but inflammasome activation appears to play an important role 29. Interestingly, intracellular oestrogen receptor-β, which is markedly increased in endometriotic tissue, enhances inflammasome-mediated interleukin-1β (IL-1β) production 30. IL-1β has in turn been shown to regulate mesothelial cell proliferation 31…”

Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

“…In pre-clinical studies, compounds that selectively target ERα and ERβ effectively block lesion growth, angiogenesis, and neurogenesis associated with endometriosis (40). Recently, ERβ gain-of-function was shown to contribute to endometriotic lesion establishment and progression by evading the immune cell surveillance in mice (41). Furthermore, the inflammatory milieu of the disease, which is characterized by elevated PGE2, activates E2 synthesis in ectopic endometriotic stromal cells via SF1 and CYP19A1 activation (25, 36, 42, 43).…”

Endometriosis: where are we and where are we going?

“…Both human and animal model studies show endometriosis is estrogen (E2) dependent and is regulated through the ESRs alpha and beta ( ESR1 and ESR2 ) (Burns et al 2012, Pellegrini et al 2012, Wu et al 2012, Han et al 2015, Zhao et al 2015). An increased ratio of ESR2 to ESR1 mRNA is observed in endometriomas compared with endometriosis implants and eutopic endometrium (Bukulmez et al 2008).…”

“…Signaling of E2 through ESR1 appears to have both an anti- and pro-inflammatory role, as observed by increased mitogenesis and decreased IFNG , TNF , and IL12 transcript expression (Burns et al 2012). Overexpression of ESR2 activates the inflammasome and modulates TNF-induced apoptosis, as observed with increases in IL1B and cleaved caspase-1 levels and decreases in cleaved caspase-8 levels in ectopic lesions (Han et al 2015). …”