Interleukin-33-Dependent Innate Lymphoid Cells Mediate Hepatic Fibrosis
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Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33's profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
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ILC2s (via IL-33), T cells (via IL-17), B cells (immunoglobulin independent), Tregs (via amphiregulin) and platelets have been suggested to directly promote HSC activation.
“Additionally, ILC2s (via IL-33), T cells (via IL-17), B cells (immunoglobulin independent), Tregs (via amphiregulin) and platelets have been suggested to directly promote HSC activation [197, 237, 242–245].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [242]
Together these data suggest complex roles for IL-33 and ILC-2 in NASH and possibly thresholds for IL-33 that need to be surpassed to modulate fibrosis.
“Together, these data suggest complex roles for IL-33 and ILC-2 in NASH and possibly thresholds for IL-33 that need to be surpassed to modulate fibrosis.”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [87]
IL-33-mediated expansion of ILC2s promotes toxin-induced liver fibrosis through an IL-13-IL4R-STAT6 pathway.
“IL-33-mediated expansion of ILC2s was shown to promote toxin-induced liver fibrosis through an IL-13-IL4R-STAT6 pathway.87”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [87]
A modified bleomycin model with intradermal injection over several weeks uncovered a substantial role for IL-4R signaling in the development of pulmonary fibrosis.
“a modified version of this model in which bleomycin is injected intra-dermally rather than intra-tracheally over several weeks uncovered a substantial role for IL-4R signaling in the development of pulmonary fibrosis141”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [141]
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- Authors
- Mchedlidze, T., Waldner, M., Zopf, S., Walker, J., Rankin, A. L., Schuchmann, M., Voehringer, D., McKenzie, A. N. J., Neurath, M. F., Pflanz, S., & Wirtz, S.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- MRC Laboratory of Molecular Biology (GB)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Wirtz, Stefan
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 39
- Issue
- 2
- Pages
- 357-371
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4172965
- OpenAlex
- W1997883939
- Cited by
- 502
- References
- 54
- Citations by year
- 2026: 13 · 2025: 33 · 2024: 30 · 2023: 33 · 2022: 35 · 2021: 37 · 2020: 46 · 2019: 43 · 2018: 48 · 2017: 50 · 2016: 47 · 2015: 47 · 2014: 35 · 2013: 4
- FWCI
- 24.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- IL-33, liver fibrosis, innate lymphoid cells, ILC2, IL-13, STAT6, hepatic stellate cells, extracellular matrix remodeling, liver inflammation, chronic liver disease
- MeSH terms
- Interleukin-33, Animals, Cells, Cultured, Inflammation, Interleukins, Liver, Liver Cirrhosis, Lymphocyte Activation, Lymphocytes, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Interleukin-13, Adoptive Transfer, Cell Proliferation, STAT6 Transcription Factor, Mice, Receptors, Interleukin-4, Type II, Hepatic Stellate Cells
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