CoChat
Sign Up
Cited by 128Liver physiology and pathologyCardiac Fibrosis and RemodelingLiver Disease Diagnosis and Treatment

IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal

Open access
Weng, Shih-Yen, Wang, Xiaoyu, Vijayan, Santosh, Tang, Yilang, Kim, Yong Ook, Padberg, Kornelius, Regen, Tommy, Molokanova, Olena +9 more·2018·EBioMedicine
DOI 10.1016/j.ebiom.2018.01.028PMC PMC5925448
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.ebiom.2018.01.028

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • IL-4Rα deficiency can paradoxically exacerbate fibrosis when present during active fibrogenesis.

    “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]

    The Results section (“IL-4Rα Deficiency Retards Progression of Liver Fibrosis”; page unavailable) reports that IL-4Rα-deficient mice developed significantly less fibrosis during active CCl4-induced progression, not more. The Discussion does mention increased fibrosis in IL-4Rα-deficient mice with chronic schistosomiasis, but identifies that as a finding from Vannella et al. (2014), a different disease context. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • IL-4 and IL-13 activate STAT6 in macrophages, leading to overexpression of the fibrolytic enzyme MMP-12.

    “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]

  • Disruption of IL-4Rα signaling has context-dependent effects: genetic deletion reduces macrophage populations and ameliorates fibrosis, while antisense-mediated inhibition during regression impairs restorative polarization and delays fibrosis resolution.

    “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]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

2 of the 60 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

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)
DOI
10.1016/j.ebiom.2018.01.028
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
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 › Epidemiology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review