Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling
Liver macrophages play a role in the development of liver fibrosis progression via the regulation of inflammatory signaling. However, the precise mechanisms of macrophages contributing to liver fibrosis progression remain unclear. Using a preclinical model of CCl4-treated mice, we determined the com...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1528382/full |
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| author | Soo-Jeung Park Josefina Garcia Diaz Josefina Garcia Diaz Tina Comlekoglu Young S. Hahn Young S. Hahn |
| author_facet | Soo-Jeung Park Josefina Garcia Diaz Josefina Garcia Diaz Tina Comlekoglu Young S. Hahn Young S. Hahn |
| author_sort | Soo-Jeung Park |
| collection | DOAJ |
| description | Liver macrophages play a role in the development of liver fibrosis progression via the regulation of inflammatory signaling. However, the precise mechanisms of macrophages contributing to liver fibrosis progression remain unclear. Using a preclinical model of CCl4-treated mice, we determined the composition of immune cells and the alteration of inflammatory gene expression. Our findings revealed a significant increase in liver macrophages, particularly those derived from infiltrating blood monocytes, in fibrotic mice. Moreover, the expression levels of type I IFN signature genes such as IFNα, IFNβ, ISG15, USP18, Ifi44, Ifit1, Ifit2, IRF3, and IRF7 were elevated in fibrotic mice. To determine the role of type I IFN signaling in liver fibrosis, we administered an IFNAR-1 antibody to block this pathway for 3 days prior to harvesting the liver. Notably, IFNAR-1 blockade reduced macrophage numbers compared to control mice and alleviated liver fibrosis in mice with increased hepatocyte proliferation and apoptosis. The ratio of P-STAT3/P-STAT1 in monocyte-derived macrophages was increased in the IFNAR-1 blockade group compared to fibrotic mice, and this was related to the appearance of M2 macrophage differentiation. Additionally, single-cell RNA-seq analysis indicated that IFNAR blockade affected inflammatory pathways involved in hepatocyte regeneration and fibrosis prevention. Taken together, IFNAR-1 blockade alleviates liver fibrosis progression by modulating macrophage inflammatory responses. These results provide insights for developing anti-fibrotic therapies against type I IFN signaling. |
| format | Article |
| id | doaj-art-0c8b1194fa8d4fc385a37309e1a88868 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-0c8b1194fa8d4fc385a37309e1a888682025-08-20T01:54:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-04-011610.3389/fimmu.2025.15283821528382Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signalingSoo-Jeung Park0Josefina Garcia Diaz1Josefina Garcia Diaz2Tina Comlekoglu3Young S. Hahn4Young S. Hahn5Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United StatesLiver macrophages play a role in the development of liver fibrosis progression via the regulation of inflammatory signaling. However, the precise mechanisms of macrophages contributing to liver fibrosis progression remain unclear. Using a preclinical model of CCl4-treated mice, we determined the composition of immune cells and the alteration of inflammatory gene expression. Our findings revealed a significant increase in liver macrophages, particularly those derived from infiltrating blood monocytes, in fibrotic mice. Moreover, the expression levels of type I IFN signature genes such as IFNα, IFNβ, ISG15, USP18, Ifi44, Ifit1, Ifit2, IRF3, and IRF7 were elevated in fibrotic mice. To determine the role of type I IFN signaling in liver fibrosis, we administered an IFNAR-1 antibody to block this pathway for 3 days prior to harvesting the liver. Notably, IFNAR-1 blockade reduced macrophage numbers compared to control mice and alleviated liver fibrosis in mice with increased hepatocyte proliferation and apoptosis. The ratio of P-STAT3/P-STAT1 in monocyte-derived macrophages was increased in the IFNAR-1 blockade group compared to fibrotic mice, and this was related to the appearance of M2 macrophage differentiation. Additionally, single-cell RNA-seq analysis indicated that IFNAR blockade affected inflammatory pathways involved in hepatocyte regeneration and fibrosis prevention. Taken together, IFNAR-1 blockade alleviates liver fibrosis progression by modulating macrophage inflammatory responses. These results provide insights for developing anti-fibrotic therapies against type I IFN signaling.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1528382/fullliver fibrosisIFNAR-1Kupffer Cellsstat3tissue repair |
| spellingShingle | Soo-Jeung Park Josefina Garcia Diaz Josefina Garcia Diaz Tina Comlekoglu Young S. Hahn Young S. Hahn Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling Frontiers in Immunology liver fibrosis IFNAR-1 Kupffer Cells stat3 tissue repair |
| title | Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling |
| title_full | Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling |
| title_fullStr | Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling |
| title_full_unstemmed | Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling |
| title_short | Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling |
| title_sort | type i ifn receptor blockade alleviates liver fibrosis through macrophage derived stat3 signaling |
| topic | liver fibrosis IFNAR-1 Kupffer Cells stat3 tissue repair |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1528382/full |
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