Int Immunopharmacol. 2022 Feb 23. pii: S1567-5769(22)00123-0. [Epub ahead of print]107
108639
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.
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.
Keywords: Antigen presentation; Endothelial cell; Immunoproteasome; Liver fibrosis; PR-957; non-alcoholic steatohepatitis (NASH)