Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.
Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.
复制标题
Nogo-B 是肝缺血和再灌注损伤的关键介质
DOI：
10.1016/j.redox.2020.101745
复制
发表时间：
2020-10
期刊：
影响因子：
11.4
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Rao J;Cheng F;Zhou H;Yang W;Qiu J;Yang C;Ni X;Yang S;Xia Y;Pan X;Zhang F;Lu L;Wang X
Nogo-B是一种内质网驻留蛋白，在不同疾病中具有独特的功能。然而，Nogo-B在肝脏无菌性炎症损伤中的作用仍不清楚。本研究旨在阐明其在肝脏缺血再灌注损伤中的作用及机制。在来自36名接受缺血相关肝切除术的患者的活检/血清标本和肝脏IRI的小鼠模型中分析Nogo-B表达和肝功能。在缺血前和再灌注后收集人标本。使用Nogo-B敲除（Nogo-BKO）和骨髓特异性Nogo-B敲除（Nogo-BMKO）小鼠来分析Nogo-B在肝IRI小鼠模型中的功能和机制。在人类标本中，Nogo-B表达与肝切除术后1天血清转氨酶（sALT）水平升高和严重的组织病理学损伤呈正相关。此外，Nogo-B主要表达于人和小鼠正常和缺血肝组织中的巨噬细胞上。与对照组不同，Nogo-BKO或Nogo-BMKO肝脏受到IRI的保护，缺血肝脏中的活性氧（ROS）产生和肝脏炎症减少。在平行的体外研究中，Nogo-B缺乏减少了M1巨噬细胞极化，并抑制了对LPS或HMGB-1刺激的促炎细胞因子（TNF-α、IL-6、MCP-1和iNOS）。机制研究表明，Nogo-B与MST 1/2结合，增加MST 1/2、LAST 1和雅普磷酸化，导致雅普活性降低。有趣的是，巨噬细胞雅普的破坏在体外和体内消除了Nogo-B缺陷介导的细胞保护作用。因此，雅普对于调节巨噬细胞Nogo-B触发的肝脏炎症是至关重要的。Nogo-B通过激活MST介导的Hippo/雅普通路，促进巨噬细胞相关的先天性炎症反应，促进IR诱导的肝损伤，为肝脏IRI的临床治疗提供了潜在的治疗靶点。肝缺血再灌注损伤（IRI）是肝移植和肝切除术后引起肝功能障碍和肝功能衰竭的主要原因，其主要表现为急性无菌性炎症和肝细胞损伤。本研究首次证明了Nogo-B在肝脏IRI中的作用和机制。Nogo-B通过激活MST介导的Hippo/雅普通路促进巨噬细胞相关的先天性炎症并促进IR诱导的肝损伤。我们的研究结果表明，Nogo-B是肝脏IRI的关键介质。
Nogo-B is an endoplasmic reticulum-residential protein with distinctive functions in different diseases. However, it remains unclear the role of Nogo-B in liver sterile inflammatory injury. This study aims to elucidate the functions and mechanisms in liver ischemia and reperfusion injury (IRI). The Nogo-B expression and liver function were analyzed in biopsy/serum specimens from 36 patients undergoing ischemia-related hepatectomy and in a mouse model of liver IRI. Human specimens were harvested prior to ischemia and post-reperfusion. The Nogo-B knockout (Nogo-BKO) and myeloid-specific Nogo-B knockout (Nogo-BMKO) mice were used to analyze the function and mechanism of Nogo-B in a mouse model of liver IRI. In human specimens, the Nogo-B expression was positively correlated with higher levels of serum transaminase (sALT) and severe histopathological injury at one day post-hepatectomy. Moreover, Nogo-B is mainly expressed on macrophages in normal and ischemic liver tissues from human and mice. Unlike in controls, the Nogo-BKO or Nogo-BMKO livers was protected against IRI, with reduced reactive oxygen species (ROS) production and liver inflammation in ischemic livers. In parallel in vitro studies, Nogo-B deficiency reduced M1 macrophage polarization and inhibited proinflammatory cytokines (TNF-α, IL-6, MCP-1 and iNOS) in response to LPS or HMGB-1 stimulation. Mechanistic studies showed that Nogo-B bound to MST1/2, increased MST1/2, LAST1, and YAP phosphorylation, leading to reduced YAP activity. Interestingly, disruption of macrophage YAP abolished Nogo-B deficiency-mediated cytoprotective effects in vitro and in vivo. Thus, YAP is crucial for the regulation of macrophage Nogo-B-triggered liver inflammation. Nogo-B promotes macrophage-related innate inflammation and contributes to IR-induced liver injury by activating the MST-mediated Hippo/YAP pathway, which provides a potential therapeutic target for clinical management in liver IRI. Liver ischemia and reperfusion injury (IRI), characterized by acute sterile inflammation and hepatocellular damage, is a major factor in initiating liver dysfunction and failure after liver transplantation and hepatectomy. This study first documented the roles and mechanisms of Nogo-B in hepatic IRI. Nogo-B promotes macrophage-related innate inflammation and contributes to IR-induced liver injury by activating the MST-mediated Hippo/YAP pathway. Our findings revealed that Nogo-B is a key mediator of hepatic IRI.
登录
查看更多内容
影响因子：
4
作者：
Paszkowiak, Jacek J.;Maloney, Stephen P.;Dardik, Alan
通讯作者：
Dardik, Alan
影响因子：
8.8
作者：
Rao, J.;Qian, X.;Lu, L.
通讯作者：
Lu, L.
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
15.9
作者：
Ramjee, Vimal;Li, Deqiang;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.
影响因子：
8.8
作者：
Lee, Ji Yun;Ismail, Ola Z.;Gunaratnam, Lakshman
通讯作者：
Gunaratnam, Lakshman