{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:49:12Z","timestamp":1782499752555,"version":"3.54.5"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"publisher","award":["112\u20132320-B-006\u2013017-MY3"],"award-info":[{"award-number":["112\u20132320-B-006\u2013017-MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"publisher","award":["114\u20132326-B-194-001"],"award-info":[{"award-number":["114\u20132326-B-194-001"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                  <jats:p>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-1\u03b2 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.<\/jats:p>","DOI":"10.1093\/reprod\/xaag072","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:18:22Z","timestamp":1781587102000},"source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-17A as a key driver for cell migration, proliferation, inflammation, and nerve infiltration in deep endometriosis"],"prefix":"10.1093","volume":"171","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1243-9587","authenticated-orcid":false,"given":"Hsiao-Chien","family":"Tang","sequence":"first","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University , Tainan,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Ning","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University , Tainan,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tin-Chien","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University , Tainan,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Hsing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University , Tainan,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Hsien","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Lucina Women & Children Hospital , Kaohsiung,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3569-5813","authenticated-orcid":false,"given":"Shaw-Jenq","family":"Tsai","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University , Tainan,","place":["Taiwan"]},{"name":"Department of Biomedical Sciences, College of Science, National Chung Cheng University , Chia-Yi,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"2026062614060746600_xaag072-B1","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.4049\/jimmunol.1501138","article-title":"IL-17A contributes to the pathogenesis of endometriosis by triggering proinflammatory cytokines and angiogenic growth factors","volume":"195","author":"Ahn","year":"2015","journal-title":"Journal of Immunology (Baltimore, Md.: 1950)"},{"key":"2026062614060746600_xaag072-B2","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1016\/j.fertnstert.2006.03.057","article-title":"Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis","volume":"86","author":"Anaf","year":"2006","journal-title":"Fertility and Sterility"},{"key":"2026062614060746600_xaag072-B3","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1093\/humrep\/15.8.1744","article-title":"Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules","volume":"15","author":"Anaf","year":"2000","journal-title":"Human Reproduction (Oxford, England)"},{"key":"2026062614060746600_xaag072-B4","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1093\/brain\/awae228","article-title":"Inflammation-induced mast cell-derived nerve growth factor: A key player in chronic vulvar pain?","volume":"148","author":"Awad-Igbaria","year":"2025","journal-title":"Brain: A Journal of Neurology"},{"key":"2026062614060746600_xaag072-B5","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1210\/js.2018-00007","article-title":"Notch-1 signaling activation and progesterone receptor expression in ectopic lesions of women with endometriosis","volume":"2","author":"Brown","year":"2018","journal-title":"Journal of the Endocrine Society"},{"key":"2026062614060746600_xaag072-B6","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1093\/humrep\/deg152","article-title":"Deep infiltrating endometriosis: Relation between severity of dysmenorrhoea and extent of disease","volume":"18","author":"Chapron","year":"2003","journal-title":"Human Reproduction (Oxford, England)"},{"key":"2026062614060746600_xaag072-B7","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1523\/JNEUROSCI.5343-11.2012","article-title":"Interleukin-17A increases neurite outgrowth from adult postganglionic sympathetic neurons","volume":"32","author":"Chisholm","year":"2012","journal-title":"The Journal of Neuroscience: The Official Journal of the Society for Neuroscience"},{"key":"2026062614060746600_xaag072-B8","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12964-020-00556-3","article-title":"Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK\/NF-kappaB signaling pathways","volume":"18","author":"Dai","year":"2020","journal-title":"Cell Communication and Signaling: CCS"},{"key":"2026062614060746600_xaag072-B9","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1093\/humrep\/deq135","article-title":"Complications, pregnancy and recurrence in a prospective series of 500 patients operated on by the shaving technique for deep rectovaginal endometriotic nodules","volume":"25","author":"Donnez","year":"2010","journal-title":"Human Reproduction (Oxford, England)"},{"key":"2026062614060746600_xaag072-B10","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/s0303-7207(99)00061-1","article-title":"Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction","volume":"151","author":"Frodin","year":"1999","journal-title":"Molecular and Cellular Endocrinology"},{"key":"2026062614060746600_xaag072-B11","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1016\/j.fertnstert.2018.08.016","article-title":"Invasion of human deep nodular endometriotic lesions is associated with collective cell migration and nerve development","volume":"110","author":"Garc\u00eda-Solares","year":"2018","journal-title":"Fertility and Sterility"},{"key":"2026062614060746600_xaag072-B12","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.jri.2016.04.289","article-title":"Increased percentage of Th17 cells in peritoneal fluid is associated with severity of endometriosis","volume":"117","author":"Gogacz","year":"2016","journal-title":"Journal of Reproductive Immunology"},{"key":"2026062614060746600_xaag072-B13","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1002\/uog.15955","article-title":"Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: A consensus opinion from the International Deep Endometriosis Analysis (IDEA) group","volume":"48","author":"Guerriero","year":"2016","journal-title":"Ultrasound in Obstetrics & Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology"},{"key":"2026062614060746600_xaag072-B14","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-026-01233-2","article-title":"Disruption of primary ciliary prostaglandin E(2) signaling by transforming growth factor-beta1 impairs endometrial receptivity","volume":"33","author":"Hou","year":"2026","journal-title":"Journal of Biomedical Science"},{"key":"2026062614060746600_xaag072-B15","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s10020-023-00772-w","article-title":"Cord blood-derived biologics lead to robust axonal regeneration in benzalkonium chloride-injured mouse corneas by modulating the Il-17 pathway and neuropeptide Y","volume":"30","author":"Huang","year":"2024","journal-title":"Molecular Medicine (Cambridge, Mass.)"},{"key":"2026062614060746600_xaag072-B16","doi-asserted-by":"publisher","first-page":"692","DOI":"10.4049\/jimmunol.1003658","article-title":"Notch signaling regulates mouse and human Th17 differentiation","volume":"187","author":"Keerthivasan","year":"2011","journal-title":"Journal of Immunology (Baltimore, Md.: 1950)"},{"key":"2026062614060746600_xaag072-B17","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.jpain.2010.08.003","article-title":"Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice","volume":"12","author":"Kim","year":"2011","journal-title":"The Journal of Pain"},{"key":"2026062614060746600_xaag072-B18","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1016\/s0015-0282(16)55436-3","article-title":"Deep endometriosis: A consequence of infiltration or retraction or possibly adenomyosis externa?","volume":"58","author":"Koninckx","year":"1992","journal-title":"Fertility and Sterility"},{"key":"2026062614060746600_xaag072-B19","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/s0015-0282(16)54244-7","article-title":"Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain","volume":"55","author":"Koninckx","year":"1991","journal-title":"Fertility and Sterility"},{"key":"2026062614060746600_xaag072-B20","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.fertnstert.2012.07.1061","article-title":"Deep endometriosis: Definition, diagnosis, and treatment","volume":"98","author":"Koninckx","year":"2012","journal-title":"Fertility and Sterility"},{"key":"2026062614060746600_xaag072-B21","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1530\/REP-18-0326","article-title":"Notch activity mediates oestrogen-induced stromal cell invasion in endometriosis","volume":"157","author":"Li","year":"2018","journal-title":"Reproduction (Cambridge, England)"},{"key":"2026062614060746600_xaag072-B22","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1093\/abbs\/gmt049","article-title":"Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages","volume":"45","author":"Li","year":"2013","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"2026062614060746600_xaag072-B23","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.2147\/JPR.S168715","article-title":"Perineural invasion in endometriotic lesions contributes to endometriosis-associated pain","volume":"11","author":"Liang","year":"2018","journal-title":"Journal of Pain Research"},{"key":"2026062614060746600_xaag072-B24","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-kappaB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct Target Ther"},{"key":"2026062614060746600_xaag072-B25","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/S1359-6446(05)03637-8","article-title":"The role of neuroinflammation in neuropathic pain: Mechanisms and therapeutic targets","volume":"11","author":"Myers","year":"2006","journal-title":"Drug Discovery Today"},{"key":"2026062614060746600_xaag072-B26","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/ni.3637","article-title":"Old dog, new tricks: IL-6 cluster signaling promotes pathogenic T(H)17 cell differentiation","volume":"18","author":"Quintana","year":"2016","journal-title":"Nature Immunology"},{"key":"2026062614060746600_xaag072-B27","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"2026062614060746600_xaag072-B28","doi-asserted-by":"publisher","first-page":"5055","DOI":"10.1523\/JNEUROSCI.3249-15.2016","article-title":"The complement system component C5a produces thermal hyperalgesia via macrophage-to-nociceptor signaling that requires NGF and TRPV1","volume":"36","author":"Shutov","year":"2016","journal-title":"The Journal of Neuroscience: The Official Journal of the Society for Neuroscience"},{"key":"2026062614060746600_xaag072-B29","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/j.fertnstert.2012.07.1117","article-title":"Interleukin-17A is present in neutrophils in endometrioma and stimulates the secretion of growth-regulated oncogene-alpha (Gro-alpha) from endometrioma stromal cells","volume":"98","author":"Takamura","year":"2012","journal-title":"Fertility and Sterility"},{"key":"2026062614060746600_xaag072-B30","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/s41590-022-01418-5","article-title":"Dermal macrophages set pain sensitivity by modulating the amount of tissue NGF through an SNX25-Nrf2 pathway","volume":"24","author":"Tanaka","year":"2023","journal-title":"Nature Immunology"},{"key":"2026062614060746600_xaag072-B31","doi-asserted-by":"publisher","first-page":"5765","DOI":"10.1210\/jcem.86.12.8082","article-title":"Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells","volume":"86","author":"Tsai","year":"2001","journal-title":"The Journal of Clinical Endocrinology and Metabolism"},{"key":"2026062614060746600_xaag072-B32","doi-asserted-by":"publisher","first-page":"105222","DOI":"10.1016\/j.jbspin.2021.105222","article-title":"Chronic pain and neuroinflammation","volume":"88","author":"Vergne-Salle","year":"2021","journal-title":"Joint Bone Spine"},{"key":"2026062614060746600_xaag072-B33","doi-asserted-by":"publisher","first-page":"15508","DOI":"10.1038\/ncomms15508","article-title":"IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression","volume":"8","author":"Wang","year":"2017","journal-title":"Nature Communications"},{"key":"2026062614060746600_xaag072-B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2021.03.003","article-title":"Interleukin-17 activates and synergizes with the notch signaling pathway in the progression of pancreatic ductal adenocarcinoma","volume":"508","author":"Wang","year":"2021","journal-title":"Cancer Letters"},{"key":"2026062614060746600_xaag072-B35","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1097\/00000478-200104000-00003","article-title":"Endometriosis of the intestinal tract: A study of 44 cases of a disease that may cause diverse challenges in clinical and pathologic evaluation","volume":"25","author":"Yantiss","year":"2001","journal-title":"The American Journal of Surgical Pathology"},{"key":"2026062614060746600_xaag072-B36","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1111\/j.1471-0528.2005.00639.x","article-title":"Peritoneal fluid concentrations of interleukin-17 correlate with the severity of endometriosis and infertility of this disorder","volume":"112","author":"Zhang","year":"2005","journal-title":"BJOG: An International Journal of Obstetrics and Gynaecology"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/reproduction\/advance-article-pdf\/doi\/10.1093\/reprod\/xaag072\/68531884\/xaag072.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/171\/6\/xaag072\/68531884\/xaag072.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/171\/6\/xaag072\/68531884\/xaag072.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:06:13Z","timestamp":1782497173000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/doi\/10.1093\/reprod\/xaag072\/8708551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6,2]]}},"URL":"https:\/\/doi.org\/10.1093\/reprod\/xaag072","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,6]]},"published":{"date-parts":[[2026,6]]},"article-number":"xaag072"}}