1. RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism
- Author
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Jie Zhang, Weilong Zhong, Simin Zhou, Xiaoyi Wang, Jingwen Zhao, Man Liu, Lu Zhang, Lu Zhou, Xin Liu, Bangmao Wang, and Hongxia Zhang
- Subjects
chemical and pharmacologic phenomena ,cytokines and chemokines ,Applied Microbiology and Biotechnology ,Mice ,Immune system ,glucocorticoid treatment ,Concanavalin A ,medicine ,immune-mediated hepatitis ,Animals ,Humans ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Hepatitis ,Chemistry ,Mechanism (biology) ,Myeloid-Derived Suppressor Cells ,Cell Biology ,medicine.disease ,Blockade ,Mice, Inbred C57BL ,Disease Models, Animal ,Hepatitis, Autoimmune ,receptor-interacting protein kinase 3 ,Liver ,Receptor-Interacting Protein Serine-Threonine Kinases ,Cancer research ,Myeloid-derived Suppressor Cell ,Female ,Research Paper ,Developmental Biology - Abstract
Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1+ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.
- Published
- 2022