The Uncoordinated-5 Homolog B Receptor Affects Hepatic Ischemia Reperfusion Injury

Klemens König,Carla Jennewein,Friedemann Kröhnert,Valbona Mirakaj,Tiago Granja,Peter Rosenberger,Nguyen Tran,David Köhler

doi:10.1371/journal.pone.0041085

Abstract

Recent evidence has demonstrated additional roles for the neuronal guidance protein receptor UNC5B outside the nervous system. Given the fact that ischemia reperfusion injury (IRI) of the liver is a common source of liver dysfunction and the role of UNC5B during an acute inflammatory response we investigated the role of UNC5B on acute hepatic IRI. We report here that UNC5B+/− mice display reduced hepatic IRI and neutrophil (PMN) infiltration compared to WT controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate- (AST) and alanine- (ALT) aminotransferase, the presence of PMN within ischemic hepatic tissue, and serum levels of inflammatory cytokines. Moreover, injection of an anti-UNC5B antibody resulted in a significant reduction of hepatic IR injury. This was associated with reduced parameters of liver injury (LDH, ALT, AST) and accumulation of PMN within the injured hepatic tissue. In conclusion our studies demonstrate a significant role for UNC5B in the development of hepatic IRI and identified UNC5B as a potential drug target to prevent liver dysfunction in the future.

Highlights

During several clinical conditions such as liver resection, liver transplantation or generalized shock, ischemia-reperfusion injury (IRI) is a common cause of liver dysfunction and hepatic failure [1]
We found a robust signal for Uncoordinated-5 homolog B (UNC5B) on neutrophil, macrophage and lymphocyte populations (Figure 1B– E)
A functional role of the neuronal guidance proteins (NGP) Receptor UNC5B was first described in the context of axonal guidance during central nervous system (CNS) development

Summary

Introduction

During several clinical conditions such as liver resection, liver transplantation or generalized shock, ischemia-reperfusion injury (IRI) is a common cause of liver dysfunction and hepatic failure [1]. Recent studies provide evidence that neuronal guidance proteins (NGP) and their receptors display an alternative class of guidance cues in the immune system that steer immune responses with regard to activation and migration of leukocytes [8,9]. NGP were first identified in the developing central nervous system (CNS), where neurons and axons are precisely guided to their final location by a balance of chemoattractive and chemorepulsive signals to establish the elaborate neuronal circuitry [10,11]. Several families of such conserved neuronal guidance cues influencing axonal migration were identified to date. This effect was not present after pre-treatment with an anti UNC5B antibody, suggesting that the protective effects of netrin-1 were mediated through an interaction with UNC5B

Methods

Results

Conclusion