{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:46:02Z","timestamp":1792712762329,"version":"4.5.0"},"reference-count":38,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32470991,82270801"],"award-info":[{"award-number":["32470991,82270801"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"crossref","award":["242300420069"],"award-info":[{"award-number":["242300420069"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["93\/4-1"],"award-info":[{"award-number":["93\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:p>\n                    Bacterial infections, particularly uropathogenic\n                    <jats:italic>E<\/jats:italic>\n                    .\n                    <jats:italic>coli<\/jats:italic>\n                    (UPEC), contribute substantially to male infertility through tissue damage and subsequent fibrosis in the testis and epididymis. The role of testicular macrophages (TMs), a diverse cell population integral to tissue maintenance and immune balance, in fibrosis is not fully understood. Here, we used single-cell RNA sequencing in a murine model of epididymo-orchitis to analyze TM dynamics during UPEC infection. Our study identified a marked increase in S100a4\n                    <jats:sup>+<\/jats:sup>\n                    macrophages, originating from monocytes, strongly associated with fibrotic changes. This association was validated in human testicular and epididymal samples. We further demonstrated that S100a4\n                    <jats:sup>+<\/jats:sup>\n                    macrophages transition to a myofibroblast-like phenotype, producing extracellular matrix proteins such as collagen I and fibronectin. S100a4, both extracellular and intracellular, activated collagen synthesis through the TGF-\u03b2\/STAT3 signaling pathway, highlighting this pathway as a therapeutic target. Inhibition of S100a4 with niclosamide or macrophage-specific\n                    <jats:italic>S100a4<\/jats:italic>\n                    KO markedly reduced immune infiltration, tissue damage, and fibrosis in infected murine models. Our findings establish the critical role of S100a4\n                    <jats:sup>+<\/jats:sup>\n                    macrophages in fibrosis during UPEC-induced epididymo-orchitis and propose them as potential targets for antifibrotic therapy development.\n                  <\/jats:p>","DOI":"10.1172\/jci193793","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T18:01:01Z","timestamp":1759255261000},"source":"Crossref","is-referenced-by-count":17,"title":["Macrophage transition to a myofibroblast state drives fibrotic disease in uropathogenic E. coli-induced epididymo-orchitis"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4913-5390","authenticated-orcid":true,"given":"Ming","family":"Wang","sequence":"first","affiliation":[{"name":"Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Chu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Henan University of Science and Technology, Luo Yang, Henan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyu","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huafei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological Sample Bank, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Daping Hospital, Army Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihao","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9088-8108","authenticated-orcid":true,"given":"Sudhanshu","family":"Bhushan","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University Giessen, Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2013686117"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4748"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmy009"},{"issue":"5","key":"B4","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.175845","article-title":"Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis","volume":"9","author":"Ghatpande","year":"2024","journal-title":"JCI 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