XBP1 Facilitating NF-κB-p65 Nuclear Translocation Promotes Macrophage-Originated Sterile Inflammation Via Regulating MT2 Transcription in the Ischemia/Reperfusion Liver

XBP1, most conserved transcription factor of endoplasmic reticulum stress, plays important roles in physiological and pathologic settings and has profound effects on disease progression and prognosis, so it is necessary to investigate XBP1 in macrophage-originated sterile inflammation during liver ischemia/reperfusion injury (IRI). Macrophage XBP1 expression and liver injury are analyzed in patients undergoing ischemia-related hepatectomy. A myeloid-specific male XBP1-knockout (XBP1 M-KO ) strain is created for function and mechanism of XBP1 on macrophage-derived sterile inflammation in murine liver IRI with in vitro parallel research. Macrophages cocultured with hypoxia-treated hepatocytes are applied to investigate impact of XBP1 in vitro, with analysis of RNA sequencing and databases. Clinically, macrophage XBP1 expression significantly increases in ischemic liver tissues and positively correlates with liver injury after hepatectomy. Less hepatocellular damage is presented in XBP1 M-KO mice than in XBP1-proficient (XBP1 FL/FL ) control animals. In vitro, XBP1 deficiency inhibits sterile inflammation and migration in macrophages cocultured with hypoxia-treated hepatocytes. Analysis of RNA sequencing and databases determines Metallothionein 2 (MT2) as XBP1 target gene, negatively regulated by binding with its promoter. XBP1 deficiency increases MT2 and IKBα expression, but inhibits nuclear factor-κB-p65 phosphorylation, markedly neutralizing XBP1 M-KO -related benefits by promoting sterile inflammation during liver IRI. XBP1 promotes macrophage-originated sterile inflammation, increases liver IRI by binding to MT2 promoter, and regulates MT2/nuclear factor-κB pathway, potentially therapeutic for clinical liver IRI.