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Published on: February 9, 2014
ADAR1 Inhibits Macrophage Apoptosis and Alleviates Sepsis-induced Liver Injury Through miR-122/BCL2A1 Signaling
Shanshou Liu1, Jiangang Xie1, Chujun Duan1
1Emergency Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Background And Aims:
As sepsis progresses, immune cell 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 sepsis-induced 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 pre-miR-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.
Insights
Adenosine deaminases acting on RNA-1 (ADAR1) reduces sepsis-induced liver injury by alleviating macrophage apoptosis via the miR-122/BCL2A1 pathway. This finding offers new therapeutic strategies for sepsis.
Area of Science:
- Immunology
- Molecular Biology
- Hepatology
Background:
- Sepsis progression involves immune cell apoptosis, contributing to immunosuppression and organ failure.
- Adenosine deaminases acting on RNA-1 (ADAR1) previously showed protective effects against sepsis-related damage.
- The specific role and mechanism of ADAR1 in sepsis-induced liver injury were not well understood.
Purpose of the Study:
- To investigate the effects of ADAR1 on immune cell activities in sepsis.
- To elucidate the mechanism by which ADAR1 influences sepsis-induced liver injury.
- To explore ADAR1's therapeutic potential in sepsis.
Main Methods:
- Transcriptome and single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from sepsis patients.
- Cecal ligation and puncture (CLP) sepsis mouse model to assess liver injury.
- In vitro studies using murine RAW 264.7 macrophages treated with lipopolysaccharide to explore ADAR1 mechanisms.
Main Results:
- Sepsis patients' PBMCs exhibited apoptotic features, with elevated ADAR1 and BCL2A1 in severe cases.
- ADAR1 overexpression alleviated liver injury and Kupffer cell apoptosis in septic mice.
- ADAR1 modulated miR-122 biosynthesis, which regulated BCL2A1, thereby reducing macrophage apoptosis via the miR-122/BCL2A1 pathway.
Conclusions:
- ADAR1 mitigates macrophage apoptosis and sepsis-induced liver damage through the miR-122/BCL2A1 signaling pathway.
- This study provides novel insights into sepsis pathogenesis and potential therapeutic targets.
- ADAR1 represents a promising target for developing interventions against sepsis-related liver injury.
