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

Alterations in estrogen-mediated cellular signaling play an essential role in the pathogenesis of endometriosis. In addition to higher estrogen receptor (ER) beta levels, enhanced ER beta activity was detected in endometriotic tissues, and the inhibition of enhanced ER beta activity by an ER beta-selective antagonist suppressed mouse ectopic lesion growth. Notably, gain of ER beta function stimulated the progression of endometriosis. As a mechanism to evade endogenous immune surveillance for cell survival, ER beta interacts with cellular apoptotic machinery in the cytoplasm to inhibit TNF-alpha-induced apoptosis. ER beta also interacts with components of the cytoplasmic inflammasome to increase interleukin-1 beta and thus enhance its cellular adhesion and proliferation properties. Furthermore, this gain of ER beta 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 ER beta function.