IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease

Hsiao Yen Ma, Gen Yamamoto, Jun Xu, Xiao Liu, Daniel Karin, Ju Youn Kim, Ludmil B. Alexandrov, Yukinori Koyama, Takahiro Nishio, Chris Benner, Sven Heinz, Sara B. Rosenthal, Shuang Liang, Mengxi Sun, Gabriel Karin, Peng Zhao, Pnina Brodt, Iain H. Mckillop, Oswald Quehenberger, Ed DennisAlan Saltiel, Hidekazu Tsukamoto, Bin Gao, Michael Karin, David A. Brenner, Tatiana Kisseleva

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Background & Aims: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. Methods: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. Results: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra–/– and major urinary protein-urokinase-type plasminogen activator/Il-17ra–/– mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. Conclusions: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. Lay summary: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.

Original languageEnglish (US)
Pages (from-to)946-959
Number of pages14
JournalJournal of Hepatology
Volume72
Issue number5
DOIs
StatePublished - May 2020
Externally publishedYes

Keywords

  • Alcoholic liver disease
  • ALD
  • Cholesterol synthesis
  • Fibrosis
  • HCC
  • Hepatocellular carcinoma
  • IL-17 signaling
  • Inflammation
  • Mutational signatures

ASJC Scopus subject areas

  • Hepatology

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  • Cite this

    Ma, H. Y., Yamamoto, G., Xu, J., Liu, X., Karin, D., Kim, J. Y., Alexandrov, L. B., Koyama, Y., Nishio, T., Benner, C., Heinz, S., Rosenthal, S. B., Liang, S., Sun, M., Karin, G., Zhao, P., Brodt, P., Mckillop, I. H., Quehenberger, O., ... Kisseleva, T. (2020). IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. Journal of Hepatology, 72(5), 946-959. https://doi.org/10.1016/j.jhep.2019.12.016