Int J Biol Sci 2022; 18(1):199-213. doi:10.7150/ijbs.65402 This issue

Research Paper

RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism

Man Liu1,2#, Hongxia Zhang1#, Lu Zhang1#, Xin Liu1, Simin Zhou1, Xiaoyi Wang1, Weilong Zhong1, Jie Zhang1, Bangmao Wang1✉, Jingwen Zhao1✉, Lu Zhou1,3✉

1. Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
2. Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
3. Department of Gastroenterology and Hepatology, People's Hospital of Hetian District, Xinjiang Uygur Autonomous Region, China.
#These authors have contributed equally to this work.

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Citation:
Liu M, Zhang H, Zhang L, Liu X, Zhou S, Wang X, Zhong W, Zhang J, Wang B, Zhao J, Zhou L. RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism. Int J Biol Sci 2022; 18(1):199-213. doi:10.7150/ijbs.65402. Available from https://www.ijbs.com/v18p0199.htm

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Abstract

Graphic 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.

Keywords: immune-mediated hepatitis, receptor-interacting protein kinase 3, myeloid-derived suppressor cells, cytokines and chemokines, glucocorticoid treatment