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 Lü, Xuehao Wang
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-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.