The Role of Interleukin-17A in the Pathogenesis of Endometriosis
Endometriosis is an estrogen-dependent, chronic inflammatory disease characterized by the ectopic presence of hormonally-responsive endometrial epithelial glands and stroma in the pelvic cavity. Theorized to arise from the phenomenon of retrograde menstruation whereby menstrual tissue is refluxed into the peritoneal cavity through the fallopian tubes, the pathogenesis of endometriosis is not only characterized by peritoneal inflammation, but its development has also been linked to abnormal immune system response that is unable to clear away menstrual debris in the pelvic cavity. Numerous studies have shown elevated levels of inflammatory cytokines and abnormally activated immune cells in the peritoneal fluid and peripheral blood of women with endometriosis. However, a comprehensive overview of immune dysfunction and inflammation in women with endometriosis is lacking. Therefore, we conducted a targeted transcriptomic profiling on the molecular pathways of inflammation and immune cell signaling to uncover pathways associated to endometriosis pathogenesis. We hypothesized that genes encoding for pro-inflammatory cytokines and immune cell activation will be abnormally expressed in patient tissue samples compared to controls. We report that indeed, genes involved in inflammation and immune cell signaling are aberrantly expressed in women with endometriosis. Further, we explored the potential involvement of interleukin-17A (IL-17A) in the pathogenesis of endometriosis. In diseases with chronic inflammation, IL-17A is known to exacerbate disease progression by promoting inflammatory cytokine production and neutrophil recruitment via the production of IL-6, IL-8, GRO-α, and G-CSF. We hypothesized that IL-17A will also exacerbate endometriosis development by promoting local inflammation. We found increased concentration of IL-17A in plasma of women with disease. It can also promote inflammatory cytokines (G-CSF, IL-6, and IL-8) in vitro. In mouse model of endometriosis, intraperitoneal injection of IL-17A did not promote proliferation of vascularization of lesions compared to controls. We also observed increased G-CSF and CD11b+Ly6C+ inflammatory monocytes in mice treated with IL-17A. As a whole, we demonstrate how eutopic endometrium and ectopic endometriotic lesions are molecularly distinct entities compared to fertile endometrium. Further, we provide novel findings on the contribution of IL-17A in peritoneal inflammation, macrophage infiltration and polarization using mouse model of endometriosis.