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.

由多种炎症反应引起的急性肝损伤 (ALI) 是一种单核细胞/巨噬细胞介导的肝损伤，与高发病率和死亡率相关。肝巨噬细胞激活是触发 ALI 的重要事件。然而，肝巨噬细胞活化的机制尚未完全阐明。本研究检测了 β-arrestin1 (ARRB1) 在脂多糖 (LPS) 诱导的 ALI野生型 (WT) 和ARRB1-敲除 ( ARRB1 -KO) 小鼠模型中的作用，ARRB1 -KO 小鼠表现出更严重的炎症损伤和与 WT 小鼠相比，肝脏巨噬细胞活化。我们发现 LPS 处理降低了 Raw264.7 和 THP-1 细胞系以及小鼠原代肝巨噬细胞中 ARRB1 的表达水平。ARRB1 的过度表达在 Raw264.7 和 THP-1 细胞系中，LPS 诱导的肝巨噬细胞活化显着减弱，例如细胞形态的转化和促炎细胞因子（肿瘤坏死因子-α、白细胞介素-1β 和白细胞介素-6）的表达增强，同时下调的ARRB1小干扰RNA和ARRB1缺乏在原发性巨噬细胞两者加重巨噬细胞活化。此外，ARRB1 的过表达抑制 LPS 诱导的肝巨噬细胞内质网 (ER) 应激，抑制 ER 应激可阻止 ARRB1 下调诱导的过度肝巨噬细胞活化。我们的数据表明，ARRB1 通过 ER 应激途径缓解 LPS 诱导的 ALI，以调节肝巨噬细胞活化，并且 ARRB1 可能是 ALI 的潜在治疗靶点。