DJ-1 deficiency attenuates expansion of liver progenitor cells through modulating the inflammatory and fibrogenic niches.

L Chen,X Sun,C Yu,J Qin,Y Wen,Q Zhang,M Luo,X Kong,J Gu,Q Xia

doi:10.1038/cddis.2016.161

Abstract

Our previous study suggested that DJ-1 has a critical role in initiating an inflammatory response, but its role in the liver progenitor cell (LPC) expansion, a process highly dependent on the inflammatory niche, remains elusive. The objective of this study is to determine the role of DJ-1 in LPC expansion. The correlation of DJ-1 expression with LPC markers was examined in the liver of patients with hepatitis B or hepatitis C virus (HBV and HCV, respectively) infection, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), cirrhosis or hepatocellular carcinoma (HCC), respectively. The role of DJ-1 in LPC expansion and the formation of LPC-associated fibrosis and inflammation was examined in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced liver injury murine model. We also determined the ability of hepatic stellate cells (HSCs) in recruiting macrophages in DJ-1 knockout (KO) mice. The expression levels of DJ-1 were upregulated in the liver of HBV, HCV, PBC and PSC patients and DDC-fed mice. Additionally, DJ-1 expression was positively correlated with LPC proliferation in patients with liver injury and mice with DDC exposure. DJ-1 has no direct effect on LPC proliferation. Reduced activation of HSCs and collagen deposition were observed in DJ-1 KO mice. Furthermore, infiltrated CD11b+Gr-1low macrophages and pro-inflammatory factors (IL-6, TNF-α) were attenuated in DJ-1 KO mice. Mechanistically, we found that HSCs isolated from DJ-1 KO mice had decreased secretion of macrophage-mobilizing chemokines, such as CCL2 and CX3CL1, resulting in impaired macrophage infiltration. DJ-1 positively correlates with LPC expansion during liver injury. DJ-1 deficiency negatively regulates LPC proliferation by impairing the formation of LPC-associated fibrosis and inflammatory niches.

Highlights

liver stem/progenitor cell (LPC) are rarely observed in the liver of healthy individuals but are ordinarily detectable in patients with nonalcoholic fatty liver disease (NAFLD), virus hepatitis and cirrhosis.[7,9,10] The livers of those patients carry remarkable continuous fibrosis and inflammatory responses
GEO data analysis suggested the positive correlation between DJ-1 and LPC proliferation in patients with NAFLD, cirrhosis and hepatocellular carcinoma (HCC) (GSE49541 and GSE17548) (Figures 1c–e)
We have demonstrated that DJ-1 expression is upregulated in the liver tissues of patients with chronic B viral or chronic C viral hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NAFLD, cirrhosis or HCC and has been associated with activated LPC proliferation

Summary

Introduction

LPCs are rarely observed in the liver of healthy individuals but are ordinarily detectable in patients with nonalcoholic fatty liver disease (NAFLD), virus hepatitis and cirrhosis.[7,9,10] The livers of those patients carry remarkable continuous fibrosis and inflammatory responses. In the rodent models, accumulating evidence has suggested that fibrogenic and inflammatory responses correlate tightly with LPC proliferation.[11] Increased α-smooth muscle actin positive (α-SMA+) matrixproducing cells and matrix deposition always serve as a positive indicator of the augment of oval cells during liver injury.[10] In addition, several crucial immune cells and their associated cytokines, such as lymphocytes, macrophages, interleukin 6 (IL-6), IL-22, tumor necrosis factor-α (TNF-α), TNF-related weak inducer of apoptosis (TWEAK), interferon. There is no direct effect of DJ-1 on LPC proliferation, we demonstrated that, by maintaining fibrogenic and inflammatory microenvironment, DJ-1 indirectly enhanced LPC expansion in a DDC-induced liver injury murine model

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Conclusion