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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Mucosal Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1528382
This article is part of the Research Topic Immunological Aspects of Fibrosis Pathogenesis: Novel Mechanisms and Therapeutic Strategies View all 15 articles
Type Ⅰ IFN receptor blockade alleviates the liver fibrosis through the macrophages derived STAT3 signaling
Provisionally accepted- University of Virginia, Charlottesville, United States
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.
Keywords: liver fibrosis, IFNAR-1, Kupffer Cells, stat3, tissue repair
Received: 14 Nov 2024; Accepted: 11 Mar 2025.
Copyright: © 2025 Park, Garcia Diaz, Comlekoglu and Hahn. 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:
Soo-Jeung Park, University of Virginia, Charlottesville, United States
Young S Hahn, University of Virginia, Charlottesville, United States
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