TWEAK and LTβ Signaling during Chronic Liver Disease

Benjamin J Dwyer,Grant A Ramm,Janina E E Tirnitz-Parker,John K Olynyk

doi:10.3389/fimmu.2014.00039

Abstract

Chronic liver diseases (CLD) such as hepatitis B and C virus infection, alcoholic liver disease, and non-alcoholic steatohepatitis are associated with hepatocellular necrosis, continual inflammation, and hepatic fibrosis. The induced microenvironment triggers the activation of liver-resident progenitor cells (LPCs) while hepatocyte replication is inhibited. In the early injury stages, LPCs regenerate the liver by proliferation, migration to sites of injury, and differentiation into functional biliary epithelial cells or hepatocytes. However, when this process becomes dysregulated, wound healing can progress to pathological fibrosis, cirrhosis, and eventually hepatocellular carcinoma. The other key mediators in the pathogenesis of progressive CLD are fibrosis-driving, activated hepatic stellate cells (HSCs) that usually proliferate in very close spatial association with LPCs. Recent studies from our group and others have suggested the potential for cytokine and chemokine cross-talk between LPCs and HSCs, which is mainly driven by the tumor necrosis factor (TNF) family members, TNF-like weak inducer of apoptosis (TWEAK) and lymphotoxin-β, potentially dictating the pathological outcomes of chronic liver injury.

Highlights

The liver possesses an extraordinary ability to orchestrate hepatocyte-mediated regeneration from acute injuries such as tissue resection or hepatic necrosis
Recent studies from our group and others have suggested the potential for cytokine and chemokine cross-talk between liver progenitor cells (LPCs) and hepatic stellate cells (HSCs), which is mainly driven by the tumor necrosis factor (TNF) family members, TNF-like weak inducer of apoptosis (TWEAK) and lymphotoxin-β, potentially dictating the pathological outcomes of chronic liver injury
SUMMARY The liver responds to chronic injury by initiating an inflammatory response, which enables the dual action of resolving injury, through the activation of fibrosis, and regeneration of injured tissue comprising the activation and differentiation of LPCs

Summary

Introduction

The liver possesses an extraordinary ability to orchestrate hepatocyte-mediated regeneration from acute injuries such as tissue resection or hepatic necrosis. The other key mediators in the pathogenesis of progressive CLD are fibrosis-driving, activated hepatic stellate cells (HSCs) that usually proliferate in very close spatial association with LPCs. Recent studies from our group and others have suggested the potential for cytokine and chemokine cross-talk between LPCs and HSCs, which is mainly driven by the tumor necrosis factor (TNF) family members, TNF-like weak inducer of apoptosis (TWEAK) and lymphotoxin-β, potentially dictating the pathological outcomes of chronic liver injury.

Results

Conclusion