Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
Cell Immunol. 2021 Sep;367:104401. doi: 10.1016/j.cellimm.2021.104401. Epub 2021 Jun 30.
Macrophages contribute to liver fibrogenesis by the production of a large variety of cytokines. ATF6 is associated with the activation of macrophages. The present study aimed to investigate the role of ATF6 in the expression of macrophage-derived cytokines and liver fibrogenesis after acute liver injury. Following thioacetamide (TAA)-induced acute liver injury, the characteristics of the occurrence of liver fibrosis and the secretion of cytokines by macrophages were first described. Then, the role of various cytokines secreted by macrophages in activating hepatic stellate cells (HSCs) was tested in vitro. Finally, endoplasmic reticulum stress (ER-stress) signals in macrophages were detected following liver injury. siRNA was used to interfere with the expression of ATF6 in macrophages to verify the influence of ATF6 on cytokine expression and liver fibrogenesis after liver injury. A single intraperitoneal injection of TAA induced acute liver injury. The depletion of macrophages attenuated acute liver injury, while it inhibited liver fibrogenesis. During acute liver injury, macrophages secrete a variety of cytokines. Most of these cytokines promoted the activation of HSCs, but the effect of IL-1α was most significant. In the early stage of acute liver injury, ER-stress signals in macrophages were activated. Interference of ATF6 expression suppressed the secretion of cytokines by macrophages and attenuated liver fibrogenesis. Overall, in the early stage of acute liver injury, ATF6 signals promoted the expression of macrophage-derived cytokines to participate in liver fibrogenesis, and IL-1α exhibited the most significant role in promoting the activation of HSCs and liver fibrogenesis.
巨噬细胞通过产生大量细胞因子促进肝纤维化。ATF6 与巨噬细胞的激活有关。本研究旨在探讨 ATF6 在急性肝损伤后巨噬细胞来源的细胞因子表达和肝纤维化发生中的作用。在硫代乙酰胺（TAA）诱导的急性肝损伤后，首先描述了肝纤维化发生的特征和巨噬细胞分泌细胞因子的特征。然后，在体外测试了巨噬细胞分泌的各种细胞因子在激活肝星状细胞（HSCs）中的作用。最后，检测了肝损伤后巨噬细胞中的内质网应激（ER-stress）信号。使用 siRNA 干扰巨噬细胞中 ATF6 的表达，以验证 ATF6 对肝损伤后细胞因子表达和肝纤维化的影响。单次腹腔注射 TAA 可诱导急性肝损伤。巨噬细胞耗竭可减轻急性肝损伤，但抑制肝纤维化。在急性肝损伤期间，巨噬细胞分泌多种细胞因子。这些细胞因子大多数促进了 HSCs 的激活，但 IL-1α 的作用最为显著。在急性肝损伤的早期，巨噬细胞中的 ER-stress 信号被激活。干扰 ATF6 表达可抑制巨噬细胞分泌细胞因子并减轻肝纤维化。总体而言，在急性肝损伤的早期，ATF6 信号促进了巨噬细胞来源的细胞因子的表达，参与肝纤维化的形成，而 IL-1α 在促进 HSCs 激活和肝纤维化形成方面表现出最显著的作用。
