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 dur...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.展开更多
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)+2 种基金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).
文摘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.
