The Role of Interleukin-33 in the Pathophysiology of Endometriosis
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Endometriosis is a debilitating condition that affects 6-10% of reproductive aged women. It is categorized by the growth of endometrial tissue outside of the uterus. There is no non-invasive diagnostic test available and treatments provide temporary relief but no cure exists. Issues surrounding endometriosis are related to the limited understanding of endometriosis pathogenesis as this is a difficult disease to recapitulate in animal models. The pathogenesis of endometriosis is theorized to occur due to retrograde menstruation, where menstrual debris is refluxed into the peritoneal cavity and instead of being cleared, this debris adheres to peritoneal surfaces. The inability to clear menstrual debris is thought to be a result of immune dysfunction. Indeed, chronic inflammation is considered hallmark feature of endometriosis. Interleukin(IL)-33 is an alarmin that has emerged as a critical regulator of several chronic inflammatory diseases. Previous reports have found that IL-33 is elevated in the plasma and peritoneal fluid of deep infiltrating endometriosis patients; however, these reports did not investigate the role, if any, of IL-33 in the disease pathophysiology. I hypothesize that IL-33 is produced by the endometriotic lesions and that IL-33 contributes to the chronic inflammation in endometriosis. Using endometriosis patient plasma and tissue samples, as well as endometrial epithelial, endothelial and endometriotic cell lines and an established syngeneic mouse model of endometriosis, I investigated the central role of IL-33 in endometriosis. My results indicate that endometriotic lesions from women with moderate/severe endometriosis produce significantly higher levels of IL-33 compared to the endometrium of healthy, fertile controls. In vitro stimulation of endometrial epithelial, endothelial and endometriotic epithelial cells with human recombinant IL-33 led to the production of pro-inflammatory and angiogenic cytokines. Additionally, stimulation of endothelial cells with IL-33 induced angiogenesis in vitro. In the syngeneic mouse model of endometriosis, intraperitoneal mouse recombinant IL-33 injections caused systemic inflammation, which manifested as an increase in plasma pro-inflammatory cytokines compared to PBS-treated control mice. Furthermore, endometriotic lesions from mouse recombinant IL-33-treated mice were highly vascularized and exhibited increased proliferation. Collectively, my studies provide convincing evidence that IL-33 perpetuates inflammation, angiogenesis and lesion proliferation, which are critical events in the lesion survival and progression of endometriosis.