Wnt2b attenuates HSCs activation and liver fibrosis through negative regulating TLR4 signaling

Yi Yuan,Qiuju Han,Zhigang Tian,Siyu Li,Jian Zhang

doi:10.1038/s41598-017-04374-5

Abstract

The Wingless-type MMTV integration site family member 2b (Wnt2b) has been found to be a principal mediator of liver development and regeneration. However, the significance of Wnt2b in the pathogenesis of fibrosis-related liver diseases remains undefined. Here, we report that Wnt2b was highly expressed in the fibrotic liver tissues, exhibiting protective effects against activation of hepatic stellate cells (HSCs) and fibrosis progression. We identified a negative regulation of Wnt2b on the toll-like receptor 4 (TLR4) activation-mediated pro-fibrogenic effects. Wnt2b was shown not only to directly suppress LPS-induced HSCs activation, but also to inhibit TLR4-enhanced the sensitivity of HSCs to transforming growth factor beta (TGF-β). Mechanistic study showed that Wnt2b suppresses TLR4 signaling through inhibiting the expression of TLR4 as well as the activation of NF-κB and MAPKs. These findings provided new insights into the pathophysiology of liver fibrosis by characterizing Wnt2b as a novel endogenous suppressor of TLR4 signaling, maintaining tissue homeostasis during the early stage of hepatic fibrosis-associated liver diseases.

Highlights

Liver fibrosis is clinically associated with the development of cirrhosis and hepatocellular carcinoma (HCC), and has become one of the most significant public health concerns worldwide[1, 2]
To investigate the potential association of Wingless-type MMTV integration site family member 2b (Wnt2b) with the development of human fibrotic liver disease, the expressions of Wnt2b were evaluated in Tissue microarrays (TMAs) containing 10 fibrotic subjects and 9 normal controls
In liver fibrosis mouse model established by repeated administration of thioacetamide (TAA) (Fig. 1b), hepatic Wnt2b expression was markedly increased compared to healthy controls, accompanied with highly expressed α-SMA (Fig. 1c)

Summary

Introduction

Liver fibrosis is clinically associated with the development of cirrhosis and hepatocellular carcinoma (HCC), and has become one of the most significant public health concerns worldwide[1, 2]. The activation of hepatic stellate cells (HSCs) is the pivotal event in liver fibrosis. Following the onset of liver injury, the quiescent vitamin A-rich HSCs are activated and differentiate to pro-fibrogenic myofibroblasts (MFBs), which are considered to be the main source of extracellular matrix (ECM) and the major effectors during fibrogenesis[4,5,6]. As an important pattern recognition receptor (PRR), TLR4 has shown to be a primary mediator for HSCs activation and fibrosis progression in the context of chronic liver injury[8, 9]. The role of Wnt2b in TLR4-associated hepatic inflammation and fibrosis-related liver diseases is still unclear. Our data demonstrate that Wnt2b may serve as a novel endogenous suppressor of TLR4 signaling-mediated liver fibrosis

Methods

Results

Conclusion