The contribution of toll‐like receptor signaling to the development of liver fibrosis and cancer in hepatocyte‐specific TAK1‐deleted mice

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Abstract
Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll‐like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation‐fibrosis‐cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor‐β‐activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4‐deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4‐deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)‐deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation‐fibrosis‐cancer axis. Surprisingly, disruption of interleukin‐1 receptor (IL‐1R) had no effect on liver injury and tumor formation, although Il1r‐deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4‐ and TLR9‐MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL‐1R signaling is crucial for the development of HCC in Tak1ΔHep mice.
Funding Information
  • National Institute of Environmental Health Sciences (P42 ES010337)
  • National Heart, Lung, and Blood Institute (T32HL134637)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085252)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA020172, R21AA025841)
  • National Natural Science Foundation of China (30500658, 81370550, 81570530)
  • American Liver Foundation
  • National Research Foundation of Korea (2017R1C1B2004423, 2017R1A5A2015541)

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