Journal Article Ahead of print
PubMed: 42298786 DOI: 10.1093/reprod/xaag072
Interleukin-17A as a key driver for cell migration, proliferation, inflammation, and nerve infiltration in deep endometriosis.
Reproduction
Authors: Hsiao-Chien Tang, Wan-Ning Li, Tin-Chien Lin, Meng-Hsing Wu, Chung-Hsien Sun, Shaw-Jenq Tsai
Affiliations
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Obstetrics and Gynecology, Lucina Women & Children Hospital, Kaohsiung, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Biomedical Sciences, College of Science, National Chung Cheng University, Chia-Yi, Taiwan.
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 to drive 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 enhances the proliferative and migratory capacities through activation of ERK1/2 and Notch1 signaling pathways. IHC staining further revealed 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 to 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. IHC staining reveals the 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.
MeSH
Endometriosis, Cells, Growth, Endometrium, Pain, Stromal Cells, Tissues, Wounds And Injuries, Reproductive Medicine, Mast Cells