The DOI matches its Crossref record; 58 of the 60 references it cites were found in a registry or an index.
IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal
Open accessAbstract
Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα −/− as well as in macrophage-specific IL-4Rα −/− (IL-4Rα ΔLysM ) mice. However, with deletion of IL-4Rα ΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression.
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“As shown by Weng et al. (65), IL-4Rα deficiency -despite its role in monocyte-to-resolutive macrophage differentiation- can paradoxically exacerbate fibrosis when present during active fibrogenesis, emphasizing the stage- and context-dependent nature of macrophage reprogramming.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [65]
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“Mechanistically, IL-4 and IL-13 were shown to activate STAT6 in macrophages, leading to overexpression of the fibrolytic enzyme MMP-12 (65).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [65]
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“Notably, disruption of IL-4Rα signaling has yielded context-dependent effects: while genetic deletion reduces macrophage populations and ameliorates fibrosis, antisense-mediated inhibition during regression impairs restorative polarization and delays fibrosis resolution (65).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [65]
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Metadata
- Authors
- Weng, S.-Y., Wang, X., Vijayan, S., Tang, Y., Kim, Y. O., Padberg, K., Regen, T., Molokanova, O., Chen, T., Bopp, T., Schild, H., Brombacher, F., Crosby, J. R., McCaleb, M. L., Waisman, A., Bockamp, E., & Schuppan, D.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- South African Medical Research Council (ZA)
- Ionis Pharmaceuticals (United States) (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Schuppan, Detlef
- ORCID
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 29
- Pages
- 92-103
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC5925448
- OpenAlex
- W2790513179
- Cited by
- 128
- References
- 60
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 11 · 2023: 18 · 2022: 17 · 2021: 21 · 2020: 9 · 2019: 15 · 2018: 4
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Gutenberg Open Science (submittedVersion, cc-by-nc-nd)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Gutenberg Open Science
- Funders
- National Science Council
- European Commission
- European Research Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- IL-4 receptor alpha, liver fibrosis, macrophage polarization, M2 macrophages, fibrosis reversal, chronic hepatitis, STAT6 signaling, MMP-12, IL-13, IL-4, inflammatory monocytes, antisense oligonucleotides, liver cirrhosis
- MeSH terms
- RAW 264.7 Cells, Animals, Disease Models, Animal, Liver Cirrhosis, Macrophage Activation, Macrophages, Spleen, Signal Transduction, Gene Expression, T-Lymphocyte Subsets, Cytokines, Mice, Knockout, Disease Progression, Matrix Metalloproteinases, Myeloid Cells, STAT6 Transcription Factor, Mice, Interleukin-4 Receptor alpha Subunit, Non-alcoholic Fatty Liver Disease
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