{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:53:24Z","timestamp":1790610804955,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hautnetz","award":["SA863\/7-1"],"award-info":[{"award-number":["SA863\/7-1"]}]},{"name":"Hautnetz","award":["FR2671\/5-1"],"award-info":[{"award-number":["FR2671\/5-1"]}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["SA863\/7-1"],"award-info":[{"award-number":["SA863\/7-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["FR2671\/5-1"],"award-info":[{"award-number":["FR2671\/5-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic non-healing wounds are characterized by persistent inflammation, excessive matrix-degrading proteolytic activity and compromised extracellular matrix (ECM) synthesis. Previous studies showed that S100A8\/A9 are strongly dysregulated in delayed wound healing and impair the proper function of immune cells. Here, we demonstrate an unrecognized pathological function of S100A9 overexpression in wounds with impaired healing that directly affects ECM functions in fibroblasts. S100A9 was analyzed in two different mouse models mimicking the features of the two most prominent types of non-healing wounds in humans. Db\/db mice were used as a model for diabetes-associated impaired wound healing. Iron-overloaded mice were used to mimic the conditions of impaired wound healing in chronic venous leg ulcers. The skin wounds of both mouse models are characterized by delayed wound closure, high and sustained expression of pro-inflammatory mediators and a substantially decreased ECM deposition, all together the hallmarks of non-healing wounds in humans. The wounds of both mouse models also present a solid and prolonged expression of S100A8 and S100A9 that coincides with a compromised ECM deposition and that was confirmed in chronic wounds in humans. Mechanistically, we reveal that S100A9 directly affects ECM deposition by shifting the balance of expression of ECM proteins and ECM degrading enzymes in fibroblasts via toll-like-receptor 4-dependent signaling. Consequently, blocking S100A9 during delayed wound healing in db\/db mice restores fibroblast ECM functions eliciting increased matrix deposition. Our data indicate that the dysregulation of S100A9 directly contributes to a compromised ECM deposition in chronic wounds and further suggests S100A9 as a promising therapeutic target to improve tissue repair in chronic wounds.<\/jats:p>","DOI":"10.3390\/ijms25189980","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T01:52:31Z","timestamp":1726624351000},"page":"9980","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dysregulated S100A9 Expression Impairs Matrix Deposition in Chronic Wounds"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3449-2723","authenticated-orcid":false,"given":"Sandra","family":"Franz","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Max B\u00fcrger Research Centre, Medical Faculty, University Leipzig, Johannisallee 30, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8412-3646","authenticated-orcid":false,"given":"Marta","family":"Torregrossa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Max B\u00fcrger Research Centre, Medical Faculty, University Leipzig, Johannisallee 30, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-9192","authenticated-orcid":false,"given":"Ulf","family":"Anderegg","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Max B\u00fcrger Research Centre, Medical Faculty, University Leipzig, Johannisallee 30, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Ertel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Max B\u00fcrger Research Centre, Medical Faculty, University Leipzig, Johannisallee 30, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1084-3875","authenticated-orcid":false,"given":"Anja","family":"Saalbach","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Max B\u00fcrger Research Centre, Medical Faculty, University Leipzig, Johannisallee 30, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wilkinson, H.N., and Hardman, M.J. 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