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) 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 TNF-α-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. [Display omitted] •ERβ function drives progression•ERβ interacts with cytoplasmic apoptotic machinery to prevent TNF-α-induced apoptosis•ERβ-inflammasome enhances adhesion and proliferates•ERβ EMT signaling induces invasion in ectopic lesions Estrogen receptor β (ERβ) plays a unique role in endometriotic tissue, where it interacts with the cytoplasmic apoptotic machinery and inflammasome complex to prevent TNF-α-induced cell death and enhance adhesion and proliferative activities of endometriotic tissues. This non-genomic action of ERβ has a predominant role in endometriosis progression.