期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 18, 期 1, 页码 199-213出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.65402
关键词
immune-mediated hepatitis; receptor-interacting protein kinase 3; myeloid-derived suppressor cells; cytokines and chemokines; glucocorticoid treatment
资金
- National Natural Science Foundation of China [81860109]
The study found that increased expression and activation of RIP3 in livers of autoimmune hepatitis patients and animal models, and inhibition of RIP3 kinase prevented immune-mediated hepatitis by promoting MDSCs infiltration with immunoregulatory properties. This indicates that RIP3 blockade may be a novel avenue for autoimmune hepatitis treatment.
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 avenue for AIH treatment.
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