Targeted inhibition of the immunoproteasome blocks endothelial MHC class II antigen presentation to CD4+ T cells in chronic liver injury.

Abstract

Chronic or overwhelming liver injury is frequently associated with fibrosis, which is the main histological characteristic of non-alcoholic steatohepatitis (NASH). Currently, there is no effective treatment for liver fibrosis. Adaptive immunity is one of the perpetrators of liver inflammation and involves the antigen-specific activation of lymphocytes. Targeting adaptive immunity has been proposed as a novel therapeutic approach for NASH. In this study, we demonstrated that liver endothelial cells contribute to MHC class II (MHC-II) antigen presentation to CD4+ T cells after chronic liver injury. In human cirrhotic liver samples, we observed an increased expression of endothelial MHC-II and of the antigen presentation-associated protein LMP7, which is one of the proteolytically active subunits of the immunoproteasome. In a CCl4-induced chronic injury model or a diet- and chemical-induced NASH model, endothelial MHC-II and LMP7 expression was induced to increase. PR-957, a selective inhibitor of the immunoproteasome, inhibited MHC-II expression in endothelial cells and CD4+ T cell response after chronic liver injury. In vitro experiment demonstrated PR-957 also reversed IFN-γ-induced upregulation of MHC-II in endothelial cells. Furthermore, PR-957 treatment or CD4+ T cell depletion in chronic liver injury alleviated liver fibrosis and reduced inflammation, as indicated by the downregulation of inflammatory response markers (F4/80, IL-1, IL-6 and IL-18). In conclusion, targeted inhibition of the immunoproteasome blocks endothelial MHC-II antigen presentation to CD4+ T cells in chronic liver injury. In this regard, the PR-957 inhibitor is a promising candidate for the development of future therapies against NASH.

• Authors: Yuwei Zhang, Xue Yang, Tao Bi, Xia Wu, Lu Wang, Yafeng Ren, Yangying Ou, Chengliang Xie, Kuangjie Li, Haolong Ran, Jing Wang, Fulan Zhao, Pixian Shui, Jie Qing
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 107 Pg. 108639 (Jun 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35219165 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier B.V.

Chemical References

• Histocompatibility Antigens Class II

Topics

• Antigen Presentation
• CD4-Positive T-Lymphocytes
• Endothelial Cells
• Graft vs Host Disease
• Histocompatibility Antigens Class II
• Humans
• Inflammation
• Liver Cirrhosis
• Non-alcoholic Fatty Liver Disease
• T-Lymphocytes