Danger signals in liver injury and restoration of homeostasis

Xiaodong Ge,Hui Han,Romain Desert,Natalia Nieto,Zhuolun Song,Sukanta Das,Dipti Athavale

doi:10.1016/j.jhep.2020.04.033

Abstract

Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.

Highlights

Detection of threats such as pathogens and cellular damage is critical to organismal survival
The liver generates and is exposed to free radicals via mitochondrial metabolism[27] and activation of membrane-bound NADPH oxidase (NOX),[28,29,30] cytoplasmic inducible nitric oxide synthase[31,32] and microsomal cytochrome P450.33,34 Maintaining a balance between free radical production and antioxidant defence is crucial in the regulation of cellular homeostasis.[26,35]
Specific damage-associated molecular patterns participate in pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer

Summary

Danger signals in liver injury and restoration of homeostasis

Hui Han[1], Romain Desert1,†, Sukanta Das1,†, Zhuolun Song1,†, Dipti Athavale1,†, Xiaodong Ge1,†, Natalia Nieto1,2,*. Summary Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can promote inflammation in the context of liver disease. We provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. We discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice. Received 24 January 2020; received in revised form 8 April 2020; accepted 23 April 2020; available online 1 May 2020

Introduction

Key point

ROS RNS Fibrosis ROS RNS HCC ROS

HCC development

NASH mtDNA ssRNA

HSC activation Profibrogenic

Neutrophil infiltration

NFκB IRF

Ductular reaction

Mesenchymal stromal cell

DAMPs in other liver cancers

Findings