MicroRNA-143-3p attenuated development of hepatic fibrosis in autoimmune hepatitis through regulation of TAK1 phosphorylation.

Hanxiao Tu,Dazhi Chen,Lina Sheng,Lanman Xu,Xiaodong Wang,Yongping Chen,Yuedong Xu,Tongtong Pan,Teng Teng,Chao Cai,Rui Wang,Zhuo Lin,Jingjing Tu,Qianjing Du,Hongwei Lin

doi:10.1111/jcmm.14750

Abstract

Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA‐143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir‐143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1‐mediated miRNA‐143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA‐143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA‐143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis.

Highlights

Autoimmune hepatitis (AIH) is a chronic disease of the liver due to body's immune system attacks liver cells and causes series con‐ sequences in the liver such as inflammation, fibrosis and even liver failure.[1]
Autoimmune hepatitis is a rare clinical syndrome of immune‐me‐ diated disorder of hepatocytes, typically with the development of auto‐antibodies,[22] and if untreated, liver damage could lead to progressive injury leading to cirrhosis, hepatic failure or even death
Chen et al shown that the mesenchymal stem cells (BMSCs) derived miR‐223‐containing exosomes con‐ tribute to liver protection in experimental autoimmune hepatitis,[28] and Wu et al found that sodium butyrate ameliorates autoimmune hepatitis through regulation of intestinal tight junction and toll‐like receptor signalling pathway.[29]

Summary

| INTRODUCTION

Autoimmune hepatitis (AIH) is a chronic disease of the liver due to body's immune system attacks liver cells and causes series con‐ sequences in the liver such as inflammation, fibrosis and even liver failure.[1]. Patients with AIH progress to cirrhosis at variable rates (ranging from 0.1% to 8.1% annually) despite treatment with immunosuppressive therapies.[4,5]. MicroRNAs (miRNAs) have been recognized as one of the most important regulators in post‐transcriptional regula‐ tion of gene expression. The mecha‐ nisms underlying these effects are not fully known, several studies have shown involvement of sprouty[3] (SPRY3)[7] and Akt/mTOR path‐ way[8] in miRNA regulation of gene expression. TAK1 is involved in the regulation of inflammation through its phosphoryla‐ tion and activation of the IkB kinase (IKK)‐NF‐κB complex and MAPK kinase.[15-17]. Whether microRNA‐143 mitigates liver inflam‐ mation and fibrosis by targeting the TAK1 in AIH is still not known. The current study examines the effect of microRNA‐143 on inflammation and fibrosis in an murine model of autoimmune hep‐ atitis. Murine hepatocytes—AML12 cell line are challenged with LPS to examine protective effects of microRNA‐143 on cells

| MATERIALS AND METHODS

F AAV8-GFP-Mir143

| DISCUSSION

Findings

CONFLICTS OF INTEREST