ADAR1 Inhibits Macrophage Apoptosis and Alleviates Sepsis-induced Liver Injury Through miR-122/BCL2A1 Signaling  

作　　者：Shanshou Liu Jiangang Xie Chujun Duan Xiaojun Zhao Zhusheng Feng Zheng Dai Xu Luo Yu Li Minghe Yang Ran Zhuang Junjie Li Wen Yin 

机构地区：[1]Emergency Department,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi,China [2]Emergency Department,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi,China [3]Third Student Brigade,School of Basic Medical Science,Fourth Military Medical University,Xi’an,Shaanxi,China [4]Department of Immunology,Fourth Military Medical University,Xi’an,Shaanxi,China

出　　处：《Journal of Clinical and Translational Hepatology》2024年第2期134-150,共17页临床与转化肝病杂志（英文版）

基　　金：supported by the Basic research program of Natural Science in Shaanxi Province(No.2020JQ-466);Key research and development program of Shaanxi Province(No.2021SF-014);University Supporting Grant(No.2020rcfczr);Basic research project of the Logistics Support Department of the Chinese Military Commission(No.BWS21J002);National Natural Science Foundation of China(No.81871587).

摘　　要：apoptosis plays regulatory roles in the pathogenesis of immunosuppression and organ failure.We previously reported that adenosine deaminases acting on RNA-1(ADAR1)reduced intestinal and splenic inflammatory damage during sepsis.However,the roles and mechanism of ADAR1 in sepsis-induced liver injury remain unclear.Methods:We performed transcriptome and single-cell RNA sequencing of peripheral blood mononuclear cells(PBMCs)from patients with sepsis to investigate the effects of ADAR1 on immune cell activities.We also employed a cecal ligation and puncture(CLP)sepsis mouse model to evaluate the roles of ADAR1 in sepsisinduced liver injury.Finally,we treated murine RAW 264.7 macrophages with lipopolysaccharide to explore the underlying ADAR1-mediated mechanisms in sepsis.Results:PBMCs from patients with sepsis had obvious apoptotic morphological features.Single-cell RNA sequencing indicated that apoptosis-related pathways were enriched in monocytes,with significantly elevated ADAR1 and BCL2A1 expression in severe sepsis.CLP-induced septic mice had aggravated liver injury and Kupffer cell apoptosis that were largely alleviated by ADAR1 overexpression.ADAR1 directly bound to premiR-122 to modulate miR-122 biosynthesis.miR-122 was an upstream regulator of BCL2A1.Furthermore,ADAR1 also reduced macrophage apoptosis in mice with CLP-induced sepsis through the miR-122/BCL2A1 signaling pathway and protected against sepsis-induced liver injury.Conclusions:The findings show that ADAR1 alleviates macrophage apoptosis and sepsis-induced liver damage through the miR-122/BCL2A1 signaling pathway.The study provides novel insights into the development of therapeutic interventions in sepsis.

关 键 词：SEPSIS MACROPHAGE ADAR1 microRNA122 BCL2A1 Apoptosis 

分 类 号：R575[医药卫生—消化系统]