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Published on: August 7, 2012
Maresin1 alleviates liver ischemia/reperfusion injury by reducing liver macrophage pyroptosis
Tong Li1, Houshuai Zeng1, Wenjing Xian2
1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
Background:
Cell pyroptosis has a strong proinflammatory effect, but it is unclear whether pyroptosis of liver macrophages exacerbates liver tissue damage during liver ischemia‒reperfusion (I/R) injury. Maresin1 (MaR1) has a strong anti-inflammatory effect, and whether it can suppress liver macrophage pyroptosis needs further study.
Methods:
This study aimed to investigate whether MaR1 can alleviate liver I/R injury by inhibiting macrophage pyroptosis. The effects of MaR1 on cell pyroptosis and mitochondrial damage were studied by dividing cells into control, hypoxia/reoxygenation, and hypoxia/reoxygenation + MaR1 groups. Knocking out RORa was used to study the mechanism by which MaR1 exert its protective effects. Transcriptome analysis, qRT‒PCR and Western blotting were used to analyze gene expression. Untargeted metabolomics techniques were used to analyze metabolite profiles in mice. Flow cytometry was used to assess cell death and mitochondrial damage.
Results:
We first found that MaR1 significantly reduced liver I/R injury. We observed that MaR1 decreased liver I/R injury by inhibiting liver macrophage pyroptosis. Then, we discovered that MaR1 promotes mitochondrial oxidative phosphorylation, increases the synthesis of ATP, reduces the generation of ROS, decreases the impairment of mitochondrial membrane potential and inhibits the opening of mitochondrial membrane permeability transition pores. MaR1 inhibits liver macrophage pyroptosis by protecting mitochondria. Finally, we found that MaR1 exerts mitochondrial protective effects through activation of its nuclear receptor RORa and the PI3K/AKT signaling pathway.
Conclusions:
During liver I/R injury, MaR1 can reduce liver macrophage pyroptosis by reducing mitochondrial damage, thereby reducing liver damage.
Insights
Maresin1 (MaR1) reduces liver injury by inhibiting liver macrophage pyroptosis and protecting mitochondria. This anti-inflammatory effect is mediated through RORa activation and the PI3K/AKT pathway.
Area of Science:
- Immunology
- Hepatology
- Cell Biology
Background:
- Cell pyroptosis, a pro-inflammatory process, may worsen liver damage during ischemia-reperfusion (I/R) injury.
- The anti-inflammatory potential of Maresin1 (MaR1) in suppressing liver macrophage pyroptosis remains under investigation.
Purpose of the Study:
- To determine if MaR1 alleviates liver I/R injury by inhibiting macrophage pyroptosis.
- To elucidate the underlying mechanisms of MaR1's protective effects.
Main Methods:
- Investigated MaR1's effects on pyroptosis and mitochondrial damage in liver cells.
- Utilized RORa knockout models to explore MaR1's mechanism of action.
- Employed transcriptome analysis, qRT-PCR, Western blotting, metabolomics, and flow cytometry.
Main Results:
- MaR1 significantly reduced liver I/R injury by inhibiting liver macrophage pyroptosis.
- MaR1 enhanced mitochondrial function, increasing ATP synthesis and reducing oxidative stress.
- MaR1 protected mitochondria by preserving membrane potential and preventing pore opening.
- MaR1's protective effects were linked to RORa activation and the PI3K/AKT pathway.
Conclusions:
- MaR1 mitigates liver I/R injury by inhibiting macrophage pyroptosis.
- MaR1 protects liver macrophages from pyroptosis through mitochondrial protection.
- Activation of RORa and the PI3K/AKT pathway mediates MaR1's protective effects against liver I/R injury.
