Type I IFN receptor blockade alleviates liver fibrosis through macrophage-derived STAT3 signaling
Open accessAbstract
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.
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An increased p-STAT3 to p-STAT1 ratio favors acquisition of a restorative phenotype.
“Accordingly, an increased phosphorylated STAT3 (p-STAT3) to phosphorylated STAT1 (p-STAT1) ratio favors acquisition of a restorative phenotype (59).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [59]
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- Authors
- Park, S.-J., Garcia Diaz, J., Comlekoglu, T., & Hahn, Y. S.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Hahn, Young S.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2025-04-07
- Volume
- 16
- Pages
- 1528382-1528382
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC12009845
- OpenAlex
- W4409239078
- Cited by
- 10
- References
- 58
- Citations by year
- 2026: 9 · 2025: 1
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute for Health and Care Research (DK122737)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- liver fibrosis, type I interferon signaling, hepatic macrophages, STAT3 signaling, M2 macrophage polarization, monocyte-derived macrophages, carbon tetrachloride-induced liver injury, hepatocyte proliferation, hepatocyte apoptosis, hepatocyte regeneration, antifibrotic therapy
- MeSH terms
- Animals, Carbon Tetrachloride, Disease Models, Animal, Liver, Liver Cirrhosis, Macrophages, Male, Mice, Inbred C57BL, Signal Transduction, STAT3 Transcription Factor, Mice, Receptor, Interferon alpha-beta
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