ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury

Yiming Lei; Sizhe Wan; Huiling Liu; Haoxiong Zhou; Lingjun Chen; Yidong Yang; Bin Wu

doi:10.1038/s41420-021-00615-9

ARRB1 suppresses the activation of hepatic macrophages via modulating endoplasmic reticulum stress in lipopolysaccharide-induced acute liver injury

Cell Death Discov. 2021 Aug 28;7(1):223. doi: 10.1038/s41420-021-00615-9.

Authors

Yiming Lei^#^{1

2}, Sizhe Wan^#^{1

2}, Huiling Liu^{1

2}, Haoxiong Zhou^{1

2}, Lingjun Chen^{1

2}, Yidong Yang^{3

4}, Bin Wu^{5

6}

Affiliations

¹ Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
² Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China.
³ Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China. yangyd6@mail.sysu.edu.cn.
⁴ Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China. yangyd6@mail.sysu.edu.cn.
⁵ Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China. wubin6@mail.sysu.edu.cn.
⁶ Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China. wubin6@mail.sysu.edu.cn.

^# Contributed equally.

Abstract

Acute liver injury (ALI) caused by multiple inflammatory responses is a monocyte-/macrophage-mediated liver injury that is associated with high morbidity and mortality. Liver macrophage activation is a vital event that triggers ALI. However, the mechanism of liver macrophage activation has not been fully elucidated. This study examined the role of β-arrestin1 (ARRB1) in wild-type (WT) and ARRB1-knockout (ARRB1-KO) mouse models of ALI induced by lipopolysaccharide (LPS), and ARRB1-KO mice exhibited more severe inflammatory injury and liver macrophage activation compared to WT mice. We found that LPS treatment reduced the expression level of ARRB1 in Raw264.7 and THP-1 cell lines, and mouse primary hepatic macrophages. Overexpression of ARRB1 in Raw264.7 and THP-1 cell lines significantly attenuated LPS-induced liver macrophage activation, such as transformation in cell morphology and enhanced expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), while downregulation of ARRB1 by small interfering RNA and ARRB1 deficiency in primary hepatic macrophages both aggravated macrophage activation. Moreover, overexpression of ARRB1 suppressed LPS-induced endoplasmic reticulum (ER) stress in liver macrophages, and inhibition of ER stress impeded excessive hepatic macrophage activation induced by downregulation of ARRB1. Our data demonstrate that ARRB1 relieves LPS-induced ALI through the ER stress pathway to regulate hepatic macrophage activation and that ARRB1 may be a potential therapeutic target for ALI.