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 sinusoidal endothelial cells (LSECs) 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 LSECs 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.

Note:
Funding Information: This work was supported by National Natural Science Foundation of China (22077106, 81700542), Sichuan Province Science and Technology Innovation Talent Project (2020JDRC0113).

Declaration of Interests: The authors have declared that no conflict of interest exists.

Ethics Approval Statement: All mouse experiments were approved by the Animal Experiment Administration Committee of Southwest Medical University (No. 2020243). The use of human liver tissue was approved by the institutional review board of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University (No. 20190307).

Keywords: liver fibrosis, non-alcoholic steatohepatitis (NASH), endothelial cell, antigen presentation, immunoproteasome, PR-957