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

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IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.jhep.2019.12.016
Hsiao-Yen Ma ₁ , Gen Yamamoto ₁ , Jun Xu ₁ , Xiao Liu ₁ , Daniel Karin ₂ , Ju Youn Kim ₃ , Ludmil B Alexandrov ₄ , Yukinori Koyama ₂ , Takahiro Nishio ₂ , Chris Benner ₂ , Sven Heinz ₂ , Sara B Rosenthal ₂ , Shuang Liang ₂ , Mengxi Sun ₂ , Gabriel Karin ₂ , Peng Zhao ₃ , Pnina Brodt ₅ , Iain H Mckillop ₆ , Oswald Quehenberger ₂ , Ed Dennis ₂ , Alan Saltiel ₃ , Hidekazu Tsukamoto ₇ , Bin Gao ₈ , Michael Karin ₃ , David A Brenner ₂ , Tatiana Kisseleva ₉

Affiliation

Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Surgery, University of California San Diego, La Jolla, CA, USA.
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Medicine, McGill University and the McGill University Health Center, Montreal, QC, Canada.
Department of Biology, University of North Carolina at Charlotte, Charlotte, NC, USA.
Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of USC, Los Angeles, CA, USA; Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Department of Surgery, University of California San Diego, La Jolla, CA, USA.

BACKGROUND&AIMS Chronic alcohol (EtOH) consumption is a leading risk factor for development of hepatocellular carcinoma (HCC), which is associated with marked increase of hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS Genetic deletion and pharmacological blocking was used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC. RESULTS We demonstrate that global deletion of IL-17RA gene suppressed HCC in alcohol-fed DEN-challenged IL-17RA-/- and Mup-uPA/IL-17RA-/- mice compared to wild type mice. When the cell-specific role of IL-17RA signaling was examined, 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-17RAΔHSCs mice (deficient of IL-17RA in hepatic stellate cells (HSCs)). 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 to IL-17RAΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated expression of Cxcl1 and other chemokines, exhibited a striking defect in TNF-TNFR1-dependent Caspase-2-SREBP-1/2-DHCR7-mediated cholesterol synthesis, and upregulated production of anti-oxidant Vitamin D3. Pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 Ab suppressed progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for treatment of alcohol-induced HCC. CONCLUSIONS Overall, IL-17A is as a tumor promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

中文翻译：

脂肪变性肝细胞和巨噬细胞中的 IL-17 信号传导促进酒精相关性肝病中的肝细胞癌

背景与目的长期饮酒 (EtOH) 是发生肝细胞癌 (HCC) 的主要危险因素，这与促炎性 IL-17A 及其受体 IL-17RA 的肝脏表达显着增加有关。方法基因缺失和药理学阻断用于表征 IL-17A/IL-17RA 信号在 HCC 发病机制中的作用。结果我们证明，与野生型小鼠相比，IL-17RA 基因的整体缺失抑制了酒精喂养的 DEN 攻击的 IL-17RA-/- 和 Mup-uPA/IL-17RA-/- 小鼠的 HCC。当检查 IL-17RA 信号传导的细胞特异性作用时，在骨髓细胞和肝细胞中缺乏 IL-17RA 的酒精喂养的 IL-17RAΔMΦ 和 IL-17RAΔHep 小鼠中，HCC 的发展减少，但在 IL-17RAΔHSCs 小鼠中没有（肝星状细胞 (HSC) 中缺乏 IL-17RA）。骨髓细胞中 IL-17RA 的缺失通过抑制酒精喂养的 IL-17RAΔMΦ 小鼠的促肿瘤/炎症和促纤维化反应来改善肿瘤发生。值得注意的是，尽管炎症反应正常，但酒精喂养的 IL-17RAΔHep 小鼠的肿瘤最少（与 IL-17RAΔMΦ 小鼠相比），脂肪变性和纤维化减少。脂肪性 IL-17RA 缺陷型肝细胞下调 Cxcl1 和其他趋化因子的表达，在 TNF-TNFR1 依赖性 Caspase-2-SREBP-1/2-DHCR7 介导的胆固醇合成中表现出显着缺陷，并上调抗氧化剂维生素 D3 的产生. 使用抗 IL-12/IL-23 Ab 药理学阻断 IL-17A/Th-17 细胞可抑制酒精喂养小鼠 HCC 的进展（70%），表明靶向 IL-17 信号可能提供新的治疗策略酒精引起的肝癌。

更新日期：2020-05-01

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