Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lab Invest. 2018 Sep;98(9):1200-1210. doi: 10.1038/s41374-018-0085-9. Epub 2018 Jun 29.
Liver fibrosis is a worldwide clinical issue. The activation of hepatic stellate cells (HSCs) is the central event during the hepatic fibrotic response. However, the exact mechanisms related to HSC activation and the connection between hepatocytes and HSCs remain unclear. We elucidated the mechanism by which the nuclear-damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1) was released from the impaired hepatocytes and induced endoplasmic reticulum stress to activate HSCs. In this work, we demonstrated that HMGB1 can be released from hepatocytes and the released HMGB1 activates the HSCs via ER stress at the transcriptional level which was dependent on the activation of both the TLR4 and RAGE signaling pathways rather than the TLR2 signaling pathway. HMGB1 induction of proinflammatory cytokines interleukin (IL)-1β and IL-18 release was dependent on ER stress. In vivo, stable inhibition of HMGB1 suppressed liver fibrosis. These results suggest that under damage condition, HMGB1 can be secreted from injured hepatocytes and activates TLR4- and RAGE signaling pathways to induce ER stress which activates HSCs. Moreover, HMGB1 can produce multiple inflammatory mediators through ER stress, which, in turn, promote liver fibrosis.
肝纤维化是一个全球性的临床问题。肝星状细胞（HSCs）的激活是肝纤维化反应过程中的核心事件。然而，与 HSCs 激活相关的确切机制以及肝细胞与 HSCs 之间的联系仍不清楚。我们阐明了核损伤相关分子模式分子高迁移率族蛋白 B1（HMGB1）从受损的肝细胞中释放并诱导内质网应激以激活 HSCs 的机制。在这项工作中，我们证明 HMGB1 可以从肝细胞中释放，并且释放的 HMGB1 通过转录水平的内质网应激激活 HSCs，这依赖于 TLR4 和 RAGE 信号通路的激活，而不是 TLR2 信号通路。HMGB1 诱导的促炎细胞因子白细胞介素（IL）-1β和 IL-18 的释放依赖于内质网应激。在体内，HMGB1 的稳定抑制可抑制肝纤维化。这些结果表明，在损伤条件下，HMGB1 可以从受损的肝细胞中分泌，并激活 TLR4 和 RAGE 信号通路，诱导内质网应激，从而激活 HSCs。此外，HMGB1 可以通过内质网应激产生多种炎症介质，进而促进肝纤维化。
