Interleukin-17A as a key driver for cell migration, proliferation, inflammation, and nerve infiltration in deep endometriosis.

In brief: Deep endometriosis is a highly invasive and severely painful disorder. This study identifies interleukin-17A as a central mediator that links immune-driven inflammation to the acquisition of pathogenic behaviors, including proliferation, invasion, and nerve infiltration, thereby the aggressive and pain-associated phenotypes of deep endometriosis. Abstract: Deep endometriosis (DE) is the most severe subtype of endometriosis, marked by aggressive cellular behavior and debilitating pain. However, the molecular mechanisms underlying DE pathogenesis remain poorly understood. In this study, we identified interleukin (IL)-17A as a critical mediator driving the pathological processes of DE. The level of IL-17A was elevated in DE tissues, with T cells, mast cells, macrophages, and endometriosis stromal cells as sources of IL-17A. Functional assays demonstrated that IL-17A stimulates the proinflammatory cytokines such as IL-1β and IL-6 as well as enhancing the proliferative and migratory capacities through activation of ERK1/2 and Notch1 signaling pathways. Immunohistochemical (IHC) staining further revealed that levels of NICD and Ki67 are abundant and positively correlates with each other in DE lesions. In addition, PGP9.5+ nerves bundles are evidently detected in DE tissues as compared with normal endometria, pelvic endometriotic lesions, and ovarian endometrioma, which reflects the nature of severe pain in DE patients. Treatment with IL-17A induces the expression of nerve growth factor (NGF), a peptide growth factor to induce nerve infiltration. The IHC staining revealed a significant positive correlation between PGP9.5+ nerves and NGF signals specifically in DE lesions. Collectively, these findings suggest that IL-17A promotes DE lesion progression by sustaining chronic inflammation and enhancing endometrial stromal cells proliferation, migration, and nerve infiltration, thereby contributing to inflammation-associated neuropathic pain in affected patients.