TNFα in liver fibrosis

Abstract

Hepatocyte death, inflammation, and liver fibrosis are the hallmarks of chronic liver disease. Tumor necrosis factor-α (TNFα) is an inflammatory cytokine involved in liver inflammation and sustained liver inflammation leads to liver fibrosis. TNFα exerts inflammation, proliferation, and apoptosis. However, the role of TNFα signaling in liver fibrosis is not fully understood. This review highlights the recent findings demonstrating the molecular mechanisms of TNFα and its downstream signaling in liver fibrosis. During the progression of liver fibrosis, hepatic stellate cells play a pivotal role in a dynamic process of production of extracellular matrix proteins and modulation of immune response. Hepatic stellate cells transdifferentiate into activated myofibroblasts in response to damaged hepatocyte-derived mediators and immune cell-derived cytokines/chemokines. Here, we will discuss the role of TNFα in hepatic stellate cell survival and activation and the crosstalk between hepatic stellate cells and hepatocytes or other immune cells, such as macrophages, dendritic cells, and B cells in the development of liver fibrosis.

Keywords: Liver fibrosis; TNFα; hepatic stellate cell; hepatocyte; macrophage.

Figure 1. Activation of TNF signaling

TNFα binding to TNFR1 causes Complex I formation by recruitment of TRADD, RIP1, TRAF2/5, cIAP1/2, and LUBAC. cIAP1/2 promotes K63-linked polyubiquitination of RIP1, whereas A20 and CYLD deubiquitinates RIP1. In the Complex I, K63-linked polyubiquitination of RIP1 mediates TAK1-TAB1-TAB2/3 complex recruitment. TAK1 is responsible for the phosphorylation and activation of IKK complex, resulting in IκBα degradation and NF-κB-mediated gene transcription. Inactivation of cIAP1 or deubiquitination of RIP1 by CYLD facilitates Complex I transition to Complex II. Complex IIa consists of TRADD, RIP1, FADD and caspase-8, which induces apoptosis. Inhibition of caspase-8 or FADD causes the formation of Complex IIb, ultimately leading to necroptosis.

Figure 2. Overview of TNFα-mediated liver fibrosis

TNFα augments HSC survival, but not activation. Hepatocyte apoptosis results in the engulfment of apoptotic bodies by macrophages and HSCs. It enhances the production of death ligands (e.g., TNFα, TRAIL and FasL) by macrophages, which further stimulates hepatocyte death. Engulfment of apoptotic bodies by HSCs increases the profibrogenic responses. TNFα-treated hepatocytes produce periostin, which can mediate collagen production in HSCs. HSCs also promote B cell survival. In fibrotic liver, B cells produce proinflammatory cytokines and chemoattractants (e.g., TNFα, IL-6, MCP-1, and MIP-1α), which can accelerate liver fibrosis.