Macrophage Nogo-B Promotes Acute Liver Inflammatory Injury By Activating Mst-Mediated Hippo/Yap Signaling

Lu ling group. Background & Aims: Nogo-B is an endoplasmic reticulum-residential protein with distinctive functions in different diseases. Its function in regulating local acute sterile inflammation remains unclear. We aimed to elucidate its role in liver IRI. Methods: The role of Nogo-B was systematically accessed in biopsy/serum specimens from 36 patients undergoing ischemia-related hepatectomy and in a mouse model of liver IRI. Human liver specimens were harvested before ischemia and after 15–30 min of ischemia and 1.5–2 h post-reperfusion. In a mouse model of liver IRI, we created Nogo-B knockout (Nogo-BKO) and myeloid-specific Nogo-B knockout (Nogo-BMKO) mice from a C57BL/6 strain to test the function and mechanism of action of Nogo-B. Results: In human specimens, high Nogo-B expression was correlated with higher levels of transaminase and severe pathological injury at one day post-hepatectomy. Furthermore, western blot, qRT-PCR, and immunofluorescence staining assaysindicated that Nogo-B is highly expressed on liver macrophages in human and mice liver tissues. Unlike in controls, Nogo-BKO and Nogo-BMKO mice were protected against IRI, with reduced reactive oxygen species (ROS) and liver inflammation in ischemic liver. In vitro, Nogo-B deficiency inhibited proinflammatory cytokines and enhanced anti-inflammatory cytokines in response to TLR4 stimulation in macrophages. Mechanistic studies showed that Nogo-B bound to MST1/2 and increased MST1/2, LATS1, and YAP phosphorylation, which in turn inhibited YAP activity. Interestingly, YAP inhibition or knockdown abolished Nogo-B deficiency-mediated anti-inflammatory effects in vitro and in vivo. Thus, Nogo-B promoted macrophage inflammatory responses via the MST-mediated Hippo/YAP pathway. Conclusions: Nogo-B contributes to liver IRI via promoting innate inflammation and hepatocellular damage by activating the MST-mediated Hippo/YAP pathway, which provides a potential therapeutic target for clinical managing liver IRI.