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

초록

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--activated kinase 1 (Tak1Hep) 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. Tak1Hep mice and Tlr4-deficient Tak1Hep mice had similar serum ALT levels, but Tlr4-deficient Tak1Hep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1Hep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1Hep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1Hep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1Hep 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 Tak1Hep 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 Tak1Hep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1Hep mice. What's new? Toll-like receptors (TLRs) are associated with chronic liver disease. Of particular interest are TLR4 and TLR9, which are suspected of having tumorigenic effects, though whether they promote the development of hepatocellular carcinoma (HCC) remains uncertain. Here, in a mouse model characterized by hepatic deletion of transforming growth factor--activated kinase 1 (Tak1Hep), recapitulating human HCC progression, deficiency of either TLR4 or TLR9 was found to block the liver inflammation-fibrosis-cancer axis. Mice lacking the adaptor molecule myeloid differentiation factor 88 also exhibited reduced liver injury and tumor growth. Meanwhile, TNF receptor type I signaling contributed to spontaneous HCC development.

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