The Role of the IL-17 and IL-33 Axis in the Pathophysiology of Endometriosis
Endometriosis is a gynecological condition characterized by the growth of endometrial tissue outside of the uterine cavity. The widely accepted theory of pathogenesis, Sampson’s theory of retrograde menstruation, postulates that menstrual effluent (ME) is refluxed into the peritoneal cavity where it adheres to peritoneal structures and develops into an endometriotic lesion. It is hypothesized that the inability to clear this ME from the peritoneal cavity is likely due to immune dysfunction. Indeed, chronic inflammation is well categorized in these patients and has simultaneously been linked to both the primary symptoms: pain and infertility, as well as hallmark features of endometriosis pathology including adhesion, invasion, cellular proliferation, neo-angiogenesis, fibrosis, and innervation. In this context, the alarmin, IL-33, as well as the pro-inflammatory cytokine, IL-17A, emerged as regulators of inflammation, angiogenesis, fibrosis, and pain in several chronic inflammatory conditions but their role in endometriosis is not well understood. Therefore, the central theme of my research was to investigate whether and how IL-33 and IL-17 independently modulate the pathophysiology of endometriosis. IL-33 acts through the ST2 receptor present on several immune cells but predominantly through group 2 innate lymphoid cells (ILC2) to promote T helper (TH) 2 cytokines. IL-17A, a predominant product of TH17 cells, acts through a heterodimeric IL-17 receptor present on immune and non-immune cells. Using a series of murine models C57Bl6, RAG2-/- (ILC sufficient) and RAG2-/-IL-2r𝛾-/- (ILC2 deficient), we showed that IL-33 perpetuates hallmark endometriosis features including inflammation, cellular proliferation, and fibrosis predominantly through ILC2. For the study of IL-17A, we utilized cell lines and murine models to show that IL-17A promotes macrophage iii recruitment and is responsible for polarizing peritoneal macrophages to an alternatively activated phenotype (M2), the predominant pathological phenotype in endometriosis. Finally, our investigations in ME samples from endometriosis patients and controls revealed that TH17 cells were less abundant in endometriosis patients. Transcriptomic analysis of immune cells further demonstrated that ME samples have dysregulated gene expression of the TH17 pathway. Overall, this thesis identifies the molecular pathways of two key pathological cytokines in endometriosis: IL-33 and IL-17A as promising non-hormonal therapeutic targets.