Positive Feedback Regulation between Transglutaminase 2 and Toll-Like Receptor 4 Signaling in Hepatic Stellate Cells Correlates with Liver Fibrosis Post Schistosoma japonicum Infection.

Zhencheng Wen,Fang Su,Guiying Lin,Juanjuan Tang,Zi Li,Dominique Ferrandon,Linzhuo Xiao,Cuiying Liang,Xiaofang Ji,Manni Wang

doi:10.3389/fimmu.2017.01808

Abstract

Liver fibrosis induced by Schistosoma japonicum (Sj) infection is characterized by the accumulation of extracellular matrix (ECM). The activated and differentiated hepatic stellate cells (HSCs) are the predominant ECM-producing cell type in the liver. Toll-like receptor (TLR) 4 pathway activation plays a key role in mice liver fibrosis models induced by alcohol, biliary ligation, and carbon tetrachloride 4. In this work, we found that TLR4 pathway activation correlated with the severity of liver fibrosis post Sj infection. The TLR4 receptor inhibitor TAK242 reduced the extent of liver fibrosis. The increased expression of TLR4, α-smooth muscle actin (α-SMA), and cytoglobin was observed in the HSCs of mouse liver after Sj infection. In response to stimulation with either lipopolysaccharide or Sj’s soluble egg antigen (SEA), high levels of TLR4 and α-SMA were induced in HSCs and were inhibited by TAK242 treatment. In previous work, we had reported that a high level of transglutaminase 2 (TGM2) is crucial for liver fibrosis post Sj infection. Herein, we found that TLR4 signaling also controlled Tgm2 expression. Inhibition of TGM2 activity by cystamine (CTM) in Sj-infected mice or in HSCs induced with all-trans-retinoic acid (ATRA) stimulation led to a lowered activation of TLR4 signaling and a reduced α-SMA expression. These results were confirmed by downregulating the Tgm2 gene by specific siRNA. These observations implied the presence of a positive feedback regulation between TGM2 and TLR4 signaling in HSCs that correlated with liver fibrosis post Sj infection. This novel connection between TGM2 and TLR4 pathway activation in liver fibrosis induced by Sj infection enhances our understanding of liver diseases.

Highlights

Schistosoma japonicum (Sj) infection has been reported in 12 provinces in China to date [1]
Consistent with the results of our previous study [19, 20], liver granuloma induced by Sj infection began at week 5, acute fibrosis began at week 6, and advanced liver fibrosis began at week 8
We found that the RNA expression level of Fn1 during Sj infection was increased at weeks 5 and 6, which correlated with the level of expression of Tgm2 and TLR4 pathway effector genes (Figure S6 in Supplementary Material)

Summary

Introduction

Schistosoma japonicum (Sj) infection has been reported in 12 provinces in China to date [1]. Sj-infected hosts display serious pathological changes in the liver. Hepatic fibrosis develops as a response to chronic liver injury or infection and occurs almost exclusively in a pro-inflammatory environment. The role of inflammatory mediators in the fibrogenic responses of the liver. The activation and proliferation of hepatic stellate cells (HSCs), which are characterized by the morphological transition to myofibroblast-like cells marked by a high level of α-SMA expression and extracellular matrix (ECM) deposition [e.g., collagen type I (COL I) and III (COL III), encoded, respectively, by the col1a1 and col3a1 genes] have been well established as central events in the pathogenesis of hepatic fibrosis [2, 3]. HSCs are the predominant ECM-producing cell type in the liver [4]. The inflammatory mechanisms that underlie the activation of HSCs and the liver fibrosis induced by Sj infection both warrant further study

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