Johnny Amer
*
Ahmad Salhab
Enas Hussini
The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1484278
This article is part of the Research Topic Immunological Aspects of Fibrosis Pathogenesis: Novel Mechanisms and Therapeutic Strategies View all 9 articles
Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity
Provisionally accepted- An-Najah National University, Nablus, Palestine
Introduction and aims: 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' vitamin D receptor (VDR) and activity alterations. Methods: Liver fibrosis was induced in BALB/C mice with carbon-tetrachloride (CCl4) for eight weeks with either vitamin D [100ng/Kg] or InVivoMAb anti-mouse OPN [100 µg/Kg] 2X/week started at week-4 of CCl4. The liver injury profile of serum ALT, AST, and inflammatory cytokines were evaluated. Histopathological findings were assessed via H&E staining and Sirius-Red staining. Fibrotic genes of αSMA, 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. Results: Following vitamin D treatment, H&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-b/IL-6/IL-4/OPN/TNF-a and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3fold decrease in αSMA, 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 overexpressed 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 αSMA, Col-III, and desmin. Conclusion: VDR expressions affect trNKT cells activity and could modulate 3 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.
Keywords: liver fibrosis, NKT cells, OPN, Vitamin D, VDR
Received: 21 Aug 2024; Accepted: 12 Nov 2024.
Copyright: © 2024 Amer, Salhab, Hussini, Shweiki, Zahran and Far. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Johnny Amer, An-Najah National University, Nablus, Palestine
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