Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity
Introduction and AimsVitamin 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.MethodsLiver fibrosis was induced in BALB/C mice with ca...
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Frontiers Media S.A.
2024-11-01
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| author | Johnny Amer Ahmad Salhab Enas Hussini Rasha Shweiki Iman Zahran Mohammad Far |
| author_facet | Johnny Amer Ahmad Salhab Enas Hussini Rasha Shweiki Iman Zahran Mohammad Far |
| author_sort | Johnny Amer |
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| description | Introduction and AimsVitamin 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.MethodsLiver fibrosis was induced in BALB/C mice with carbon-tetrachloride (CCl4) for 8 weeks with either vitamin D [100 ng/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.ResultsFollowing 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-β/IL-6/IL-4/OPN/TNF-α and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3-fold 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 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 αSMA, Col-III, and desmin.ConclusionVDR 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. |
| format | Article |
| id | doaj-art-7501220f5645476b8a5cd6b9f2bfcdb4 |
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| spelling | doaj-art-7501220f5645476b8a5cd6b9f2bfcdb42025-08-20T01:53:21ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-11-011510.3389/fphar.2024.14842781484278Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activityJohnny Amer0Ahmad Salhab1Enas Hussini2Rasha Shweiki3Iman Zahran4Mohammad Far5Department of Allied and Applied Medical Sciences, Division of anatomy, Biochemistry and Genetics, An-Najah National University, Nablus, PalestineDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, PalestineDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, PalestineDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, PalestineDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, PalestineDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, PalestineIntroduction and AimsVitamin 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.MethodsLiver fibrosis was induced in BALB/C mice with carbon-tetrachloride (CCl4) for 8 weeks with either vitamin D [100 ng/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.ResultsFollowing 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-β/IL-6/IL-4/OPN/TNF-α and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3-fold 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 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 αSMA, Col-III, and desmin.ConclusionVDR 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.https://www.frontiersin.org/articles/10.3389/fphar.2024.1484278/fullliver fibrosisNKT cellsOPNvitamin DVDR |
| spellingShingle | Johnny Amer Ahmad Salhab Enas Hussini Rasha Shweiki Iman Zahran Mohammad Far Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity Frontiers in Pharmacology liver fibrosis NKT cells OPN vitamin D VDR |
| title | Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity |
| title_full | Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity |
| title_fullStr | Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity |
| title_full_unstemmed | Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity |
| title_short | Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity |
| title_sort | osteopontin neutralization increases vitamin d receptors on nkt cells and ameliorates liver fibrosis by promoting their activity |
| topic | liver fibrosis NKT cells OPN vitamin D VDR |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1484278/full |
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