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

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

iScience. 2021 Apr 29;24(5):102483. doi: 10.1016/j.isci.2021.102483. eCollection 2021 May 21.

Authors

Anteneh Getachew^{1

2

3

4}, Nasir Abbas^{1

2

3

4}, Kai You^{1

3

4}, Zhen Yang^{1

2

3

4}, Muzammal Hussain^{2

4}, Xinping Huang^{1

2

3

4}, Ziqi Cheng^{1

2

3

4}, Shenglin Tan^{1

2

3

4}, Jiawang Tao^{1

2

3

4}, Xiaorui Yu^{1

2

3

4}, Yan Chen^{1

3

4}, Fan Yang^{1

3

4}, Tingcai Pan^{1

3

4}, Yingying Xu^{1

3

4}, Guosheng Xu^{1

3

4}, Yuanqi Zhuang^{1

3

4}, FeiMa Wu^{1

3

4}, Yinxiong Li^{1

2

3

4

5}

Affiliations

¹ Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.
² University of China Academy of Sciences, Beijing 100049, China.
³ Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
⁴ Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
⁵ Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.

Abstract

Hepatic 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.

Keywords: Biochemistry; Cell biology; Cell engineering.