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

Jianhua Rao; Zeng Wang; Fei Yu; Junda Li; Wenzhu Li; Zhengfeng Xuan; Yongquan Chi; Feng Zhang; Liming Tang; Feng Cheng

Cellular and Molecular Gastroenterology and Hepatology (Jan 2024)

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

Jianhua Rao,
Zeng Wang,
Fei Yu,
Junda Li,
Wenzhu Li,
Zhengfeng Xuan,
Yongquan Chi,
Feng Zhang,
Liming Tang,
Feng Cheng

Affiliations

Jianhua Rao: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jianhua Rao, MD, Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.
Zeng Wang: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Center of Gastrointestinal Disease, The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, Changzhou, China
Fei Yu: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Junda Li: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Wenzhu Li: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Zhengfeng Xuan: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Yongquan Chi: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Feng Zhang: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Liming Tang: Center of Gastrointestinal Disease, The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, Changzhou, China; Liming Tang, MD, Center of Gastrointestinal Disease, The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, Changzhou 213003, China.
Feng Cheng: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Correspondence Address correspondence to: Feng Cheng, MD, Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.

Journal volume & issue: Vol. 18, no. 6
p. 101402

Abstract

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Background & Aims: 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. Methods: A myeloid-specific male XBP1-knockout (XBP1M-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. Results: Clinically, macrophage XBP1 expression significantly increases in ischemic liver tissues and positively correlates with liver injury after hepatectomy. Less hepatocellular damage is presented in XBP1M-KO mice than in XBP1-proficient (XBP1FL/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 XBP1M-KO-related benefits by promoting sterile inflammation during liver IRI. Conclusions: 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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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