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Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells

Cellular & Molecular Immunology volume 15, pages 388–398 (2018)Cite this article

Abstract

Liver fibrosis is a consequence of chronic liver disease, causing morbidity and mortality. Interleukin-33 (IL-33) is a critical mediator of inflammation, which may be involved in the development of liver fibrosis. Here, we investigated the role of IL-33 in human patients and experimental bile-duct ligation (BDL)-induced fibrosis in mice. We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis. Liver injury, inflammatory cell infiltration and fibrosis were reduced in the absence of the IL-33/ST2 receptor, and the activation of hepatic stellate cells (HSCs) was decreased in ST2-deficient mice. Recombinant IL-33 activated HSCs isolated from C57BL/6 mice, leading to the expression of IL-6, TGF-β, α-SMA and collagen, which was abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling. Finally, administration of recombinant IL-33 significantly increased hepatic inflammation in sham-operated BL6 mice but did not enhance BDL-induced hepatic inflammation and fibrosis. In conclusion, BDL-induced liver inflammation and fibrosis are dependent on ST2 signaling in HSCs, and therefore, the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation (81502036 to ZT, 81201595 to SS, 81201528 to RJ), the Natural Science Foundation of Jiangsu Province (BK20151031 to ZT), the National Key Research and Development Program of China (2016YFC0905900 to BS), the State Key Program of National Natural Science of China (81430062 to BS) and the project of the Nanjing Science and Technology Development Plan (201303033 to LL). The work was also supported in part by the Program for Development of Innovative Research Teams in the First Affiliated Hospital of NJMU, the Priority Academic Program of Jiangsu Higher Education Institutions and funds from CNRS and FEDER (BR).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Living Donor Liver Transplantation, Department of Liver Surgery, National Health and Family Planning Commission, The First Affiliated Hospital of Nanjing Medical University,, Nanjing, Jiangsu, P.R. China

    Zhongming Tan, Qianghui Liu, Runqiu Jiang, Long Lv, Siamak S Shoto, Junwei Tang, Wenjie Zhang & Beicheng Sun

  2. Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France

    Zhongming Tan, Qianghui Liu, Isabelle Maillet, Valerie Quesniaux & Bernhard Ryffel

  3. IIDMM, University of Cape Town, Cape Town, South Africa

    Zhongming Tan, Qianghui Liu & Bernhard Ryffel

  4. Department of General Surgery, People’s Hospital of Gaochun, Nanjing, Jiangsu, P.R. China

    Long Lv

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  1. Zhongming Tan
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Contributions

Qianghui Liu and Zhongming Tan performed the study and wrote the paper; Runqiu Jiang and Long Lv contributed to clinical sample collection and analysis; Siamak S. Shoto, Junwei Tang and Wenjie Zhang contributed to HSC isolation; Isabelle Maillet conducted FACS analysis; Valerie Quensiaux contributed to the revision of the paper; Bernhard Ryffel and Beicheng Sun designed and supervised the study.

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Correspondence to Beicheng Sun or Bernhard Ryffel.

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Tan, Z., Liu, Q., Jiang, R. et al. Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells. Cell Mol Immunol 15, 388–398 (2018). https://doi.org/10.1038/cmi.2016.63sr

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