SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury

Anteneh Getachew,Nasir Abbas,Kai You,Zhen Yang,Muzammal Hussain,Xinping Huang,Ziqi Cheng,Shenglin Tan,Jiawang Tao,Xiaorui Yu,Yan Chen,Fan Yang,Tingcai Pan,Yingying Xu,Guosheng Xu,Yuanqi Zhuang,Feima Wu,Yinxiong Li

doi:10.1016/j.isci.2021.102483

Abstract

SummaryHepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.

Highlights

Hepatic fibrosis is a manifestation of wound repair in chronic liver insults resulting from overproduction of the extracellular matrix (ECM) by activated hepatic stellate cells (HSCs) (Bataller and Brenner, 2005; Mencin et al, 2009)
Gene knockdown efficiently suppressed serum amyloid A1 (SAA1) expression in mice models of acute liver injury To elucidate the specific activity of SAA1 in recruitment of HSCs responding to injury, we applied a stealth RNAiä siRNA technology to suppress the expression of SAA1 in CCl4 and cryoinjury mice models
From IHC analysis, we found that SAA1 expression was accompanied by considerable recruitment of activated HSCs within 2 days after injury induction (Figures S1A and S1B)

Summary

Introduction

Hepatic fibrosis is a manifestation of wound repair in chronic liver insults resulting from overproduction of the extracellular matrix (ECM) by activated hepatic stellate cells (HSCs) (Bataller and Brenner, 2005; Mencin et al, 2009). Quiescent HSCs undergo an activation process and transdifferentiate into a myofibroblast phenotype characterized by increased proliferation and migration (Border and Noble, 1994; Rojkind et al, 1983) This process is mediated by cytokines and chemokines, which are predominantly produced by injured hepatocytes and infiltrating immune cells and by HSCs themselves (Geerts, 2001; Lemoinne et al, 2013). In the settings of chronic injury, HSCs continuously migrate within hepatic lobule into injury sites and deposit excessive ECM (Lemoinne et al, 2013) If this recurrent migration and deposition of ECM by HSCs cannot be shutdown, the resultant tissue scaring and neoplasia, rather than the healing process, impair the regenerative capacity and increase the chance for cirrhosis (Border and Noble, 1994). Despite remarkable progress in the field, signals mediating migration of HSCs as well as mechanisms orchestrating various facets of the fibrogenic process are still ill-defined

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