{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:12:43Z","timestamp":1770747163873,"version":"3.49.0"},"reference-count":65,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gluck Equine Research Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"2024 Equine Research Award \u2013 Boehringer Ingelheim","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"USDA Capacity Project","award":["HATCH #7009671"],"award-info":[{"award-number":["HATCH #7009671"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ascending placentitis is a significant cause of equine pregnancy loss, yet the upstream inflammatory triggers are poorly defined. Recently, we identified S100A8\/S100A9 (S100A8\/A9) alarmins as potential upstream regulators in a chronic equine placentitis model. The current study aimed to determine whether this upregulation is sustained in the acute model and in clinical cases, and to elucidate the expression of their downstream inflammatory mediators. Using an experimental model, we quantified S100A8\/A9 mRNA expression in acute (n = 5) and chronic (n = 6) placentitis induced by Streptococcus equi ssp. zooepidemicus. We found mRNA expression of S100A8 and S100A9 was significantly upregulated in chorioallantois during both acute (p &lt; 0.001) and chronic (p &lt; 0.0001) disease compared to controls (n = 5), demonstrating their role is not limited to chronic pathology. A strong positive correlation (r = 0.945) underscored their coordinated expression. Immunohistochemistry revealed minimal staining in controls but dense infiltrations of S100A8\/A9-positive neutrophils and macrophages in placentitis tissues. To define the clinical relevance of the downstream pathway, we analyzed RNA sequencing data from clinical placentitis cases (placentitis, n = 4) compared to normal postpartum placenta (control, n = 4). This confirmed upregulation of S100A8\/A9 and revealed a concurrent increase in their receptors (TLR4, RAGE) and a spectrum of NF-\u03baB-driven effectors, including pro-inflammatory cytokines (IL1\u03b2, IL6, TNF), chemokines (CXCL8, CCL2, CXCL10), and the apoptotic mediator CASP3. Our findings establish that S100A8\/A9 upregulation is a sustained feature of equine placentitis and delineates a coherent S100A8\/A9-TLR4\/RAGE-NF-\u03baB signaling axis that drives inflammation and tissue damage in clinical disease. These findings highlight the diagnostic potential of S100A8\/A9 and position this alarmin system as a promising therapeutic target for mitigating infection-induced pregnancy loss.<\/jats:p>","DOI":"10.3390\/ijms27031550","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:20:14Z","timestamp":1770225614000},"page":"1550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of the S100A8\/A9 Alarmin Amplifies Inflammatory Pathways in Equine Ascending Placentitis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-641X","authenticated-orcid":false,"given":"Kirsten E.","family":"Scoggin","sequence":"first","affiliation":[{"name":"Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimaa I.","family":"Rakha","sequence":"additional","affiliation":[{"name":"Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9235-2449","authenticated-orcid":false,"given":"Ahmed M.","family":"Abdellatif","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatma","family":"Adlan","sequence":"additional","affiliation":[{"name":"Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-5418","authenticated-orcid":false,"given":"Yosra A.","family":"Helmy","sequence":"additional","affiliation":[{"name":"Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Ruby","sequence":"additional","affiliation":[{"name":"Veterinary Diagnostic Laboratory, University of Kentucky, Lexington, KY 40511, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0502-0276","authenticated-orcid":false,"given":"Barry","family":"Ball","sequence":"additional","affiliation":[{"name":"Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9130-4752","authenticated-orcid":false,"given":"Yatta","family":"Boakari","sequence":"additional","affiliation":[{"name":"Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A & M University, College Station, TX 77843, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-488X","authenticated-orcid":false,"given":"Hossam El-Sheikh","family":"Ali","sequence":"additional","affiliation":[{"name":"Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1071\/RD18400","article-title":"Small RNA (sRNA) expression in the chorioallantois, endometrium and serum of mares following experimental induction of placentitis","volume":"31","author":"Loux","year":"2019","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1439-0531.2010.01633.x","article-title":"Ascending placentitis in the mare: An update","volume":"45","author":"LeBlanc","year":"2010","journal-title":"Reprod. Domest. 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