{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T22:44:31Z","timestamp":1792709071630,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Granulomatous lobular mastitis (GLM) is a nonspecific chronic inflammatory breast disorder with an obscure etiology and pathogenesis. Neutrophil extracellular traps (NETs), which are extracellular web-like structures composed of decondensed chromatin and granular proteins released by activated neutrophils, disrupt normal tissue architecture and perpetuate inflammatory responses. The aim of the present study was to explore the role of NETs in GLM and the underlying regulatory mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Neutrophils were isolated from the blood of GLM patients and healthy controls (HCs) to assess NET formation. The presence of NETs in GLM tissues was detected using Western blot, immunohistochemistry, and immunofluorescence analyses. A mouse model of GLM was established to determine whether the inhibition of NET production, which is dependent on S100A8\/S100A9, alleviates mammary gland inflammation. The potential mechanisms and therapeutic implications were further explored through\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NETs were significantly increased in GLM tissues, as characterized by elevated levels of citrullinated histone H3 (CitH3) and myeloperoxidase (MPO). S100A8\/S100A9 was highly expressed in GLM and demonstrated significant diagnostic value alongside NET markers. Mechanistically, S100A8\/S100A9 promoted NETosis through interactions with peptidylarginine deiminase 4 (PAD4). Both paquinimod (an S100A8\/S100A9 inhibitor) and Cl-amidine (a PAD4 inhibitor) effectively suppressed NET formation\n                      <jats:italic>in vitro<\/jats:italic>\n                      . In the GLM mouse model, both inhibitors reduced mammary gland inflammation, NET accumulation, and tissue damage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The present findings indicated that NETs contribute to the pathogenesis of GLM. S100A8\/S100A9 plays a critical role in promoting NET formation via PAD4 activation. Targeting this axis with paquinimod effectively inhibits NETosis and alleviates GLM, suggesting a promising therapeutic strategy for GLM and other inflammatory diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1672538","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T06:28:05Z","timestamp":1765866485000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["S100A8\/S100A9 through PAD4 activation of neutrophil extracellular traps promotes granulomatous lobular mastitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Tingting","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwen","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-007-9116-1","article-title":"Idiopathic granulomatous mastitis: a heterogeneous disease with variable clinical presentation","volume":"31","author":"Baslaim","year":"2007","journal-title":"World J Surg"},{"key":"B2","doi-asserted-by":"publisher","first-page":"158","DOI":"10.21037\/atm-22-6473","article-title":"Identification of periductal mastitis and granulomatous lobular mastitis: a literature review","volume":"11","author":"Jiao","year":"2023","journal-title":"Ann Transl Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1309\/AJCP1W9JBRYOQSNZ","article-title":"Cystic neutrophilic granulomatous mastitis: an underappreciated pattern strongly associated with gram-positive bacilli","volume":"136","author":"Renshaw","year":"2011","journal-title":"Am J Clin Pathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/ans.14115","article-title":"Factors related to recurrence of idiopathic granulomatous mastitis: what do we learn from a multicentre study","volume":"88","author":"Uysal","year":"2018","journal-title":"ANZ J Surg"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.14194","article-title":"Erythema nodosum in association with idiopathic granulomatous mastitis: a case series and review of the literature","volume":"31","author":"Fruchter","year":"2017","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.bpobgyn.2021.11.013","article-title":"Inflammatory diseases of the breast","volume":"83","author":"Scott","year":"2022","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamcollsurg.2007.07.041","article-title":"Idiopathic granulomatous mastitis: a 25-year experience","volume":"206","author":"Al-Khaffaf","year":"2008","journal-title":"J Am Coll Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00595-011-0046-z","article-title":"Granulomatous mastitis: is it an autoimmune disease? 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