{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:14:38Z","timestamp":1780107278659,"version":"3.54.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"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. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction and Aims<\/jats:title><jats:p>Vitamin D has an immunomodulatory property influencing the activity of NKT cells. We aimed to study the impact of osteopontin (OPN), a key driver of fibrosis, on NKT cells\u2019 vitamin D receptor (VDR) and activity alterations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Liver fibrosis was induced in BALB\/C mice with carbon-tetrachloride (CCl<jats:sub>4<\/jats:sub>) for 8\u00a0weeks with either vitamin D [100\u00a0ng\/kg] or InVivoMAb anti-mouse OPN [100\u00a0\u03bcg\/kg] 2X\/week started at week-4 of CCl<jats:sub>4.<\/jats:sub> The liver injury profile of serum ALT, AST, and inflammatory cytokines were evaluated. Histopathological findings were assessed via H&amp;amp;E staining and Sirius-Red staining. Fibrotic genes of \u03b1SMA, CREBP, and collagen III were assessed using RT-PCR. Fast blood sugar, insulin, liver cholesterol, and triglyceride were evaluated. Liver tissue-resident (tr)-NKT cells were obtained for VDR expressions, molecular pathways of p-STAT1 and P-STAT-5, and activation markers of CD107a and NKp46 using flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Following vitamin D treatment, H&amp;amp;E staining revealed reduced microvascular and macrovascular steatosis, while Sirius-Red staining showed less fibrosis accumulation in liver fibrosis mice than in untreated counterparts. Results were associated with a significant decrease in serum cytokines of IL-\u03b2\/IL-6\/IL-4\/OPN\/TNF-\u03b1 and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3-fold decrease in \u03b1SMA, CREB, and Col-III in liver fibrosis mice following vitamin D treatment. Quantitated liver cholesterol and triglycerides, serum insulin, and fasting blood sugar ameliorated their levels following vitamin D treatment in liver fibrosis mice. OPN-neutralizing antibody over-expressed VDR on trNKT cells and increased CD107a and NKp46 activities of 3.1 and 3.5 folds, respectively, associated with increasing in p-STAT1 and p-STAT5 phosphorylation. These results were accompanied with a decrease in hepatic-stellate-cell activation markers of \u03b1SMA, Col-III, and desmin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>VDR expressions affect trNKT cells activity and could modulate progressions of liver fibrosis. Using an OPN-neutralizing antibody exhibited an antifibrotic effect by alleviating the liver injury profile through NKT cells. It is also suggested as an immunomodulatory target of liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1484278","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T04:26:37Z","timestamp":1732508797000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity"],"prefix":"10.3389","volume":"15","author":[{"given":"Johnny","family":"Amer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Salhab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enas","family":"Hussini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha","family":"Shweiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Zahran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Far","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8465","DOI":"10.3390\/ijms23158465","article-title":"Vitamin D-VDR novel anti-inflammatory molecules-new insights into their effects on liver diseases","volume":"23","author":"Aggeletopoulou","year":"2022","journal-title":"Int. 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