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

Abstract 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.