Nogo-B is a key mediator of hepatic ischemia and reperfusion injury

Jianhua Rao; Feng Cheng; Haoming Zhou; Wenjie Yang; Jiannan Qiu; Chao Yang; Xuehao Ni; Shikun Yang; Yongxiang Xia; Xiongxiong Pan; Feng Zhang; Ling Lu; Xuehao Wang

doi:10.1016/j.redox.2020.101745

Nogo-B is a key mediator of hepatic ischemia and reperfusion injury

Redox Biol. 2020 Oct:37:101745. doi: 10.1016/j.redox.2020.101745. Epub 2020 Oct 8.

Authors

Affiliations

¹ Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, 210029, China.
² Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, 210029, China. Electronic address: Lvling@njmu.edu.cn.
³ Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, 210029, China. Electronic address: Wangxh@njmu.edu.cn.

Abstract

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-B^KO) and myeloid-specific Nogo-B knockout (Nogo-B^MKO) 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-B^KO or Nogo-B^MKO 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.

Keywords: Hepatic ischemia/reperfusion injury; Hippo/YAP signaling; Inflammation; MST1/2; Macrophage; Nogo-B.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Ischemia
Liver
Liver Diseases*
Mice
Mice, Inbred C57BL
Reperfusion Injury*
Signal Transduction