Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma

Shuixia Tan,Heling Pan,Yedan Zhong,Shuangyi Cao,Kongyan Niu,Jing Zhao,Nan Liu,Junhao Hu,Linyu Shi,Lihui Qian,Junying Yuan,Han Wang,Ziyu Sun

doi:10.1073/pnas.2005353117

Abstract

Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

Highlights

Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis
We found that TAK1 protein levels in hepatocytes of Tak1ΔHEP mice were markedly decreased, which was not affected by RIPK1 D138N mutation in Tak1ΔHEP;Ripk1D138N/D138N mice (SI Appendix, Fig. S1A)
These results suggest that TAK1 deficiency promotes hepatocytes to undergo RIPK1-dependent apoptosis (RDA)

Summary

Introduction

Transforming growth factor β-activated kinase (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Inhibition of RIPK1, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. HCC development has been attributed to chronic liver damage induced by hepatocyte death and inflammation, which in turn drives cirrhosis and fibrosis as well as compensatory proliferation [2]. RIPK1 (receptor interacting protein kinase 1) plays important roles in mediating cell death, including necroptosis and RIPK1-dependent apoptosis (RDA) [11, 12]. CCL2 knockout mice have been shown to be highly resistant to chronic

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Conclusion