肝损伤
抗原呈递
免疫学
MHC II级
炎症
抗原
下调和上调
MHC I级
内皮干细胞
T细胞
纤维化
生物
主要组织相容性复合体
医学
癌症研究
免疫系统
病理
内分泌学
体外
生物化学
基因
作者
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
标识
DOI:10.1016/j.intimp.2022.108639
摘要
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.
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