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FOXO1通过AKT/Stat3/FOXO1信号通路调节Th17/Treg比例减轻肝脏缺血再灌注损伤。

FOXO1 Alleviates Liver Ischemia-reperfusion Injury by Regulating the Th17/Treg Ratio through the AKT/Stat3/FOXO1 Pathway.

作者信息

Ren Hao-Zhen, Xia Sen-Zhe, Qin Xue-Qian, Hu An-Yin, Wang Jing-Lin

机构信息

Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.

Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China.

出版信息

J Clin Transl Hepatol. 2022 Dec 28;10(6):1138-1147. doi: 10.14218/JCTH.2021.00551. Epub 2022 Mar 15.

DOI:10.14218/JCTH.2021.00551
PMID:36381102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9634774/
Abstract

BACKGROUND AND AIMS

Hepatic ischemic reperfusion injury (IRI) occurring during surgery seriously affects patient prognosis. The specific mechanism of IRI has not been fully elucidated. The study aim was to explore the changes of inflammatory environment, and the relationship of the Th17/Treg cell ratio and FOXO1 expression in hepatic IRI.

METHODS

Liver samples at different ischemic times were collected from patients and mice. The expression of inflammatory markers and FOXO1 in the liver was detected by western blotting and qPCR. Phenotypic changes of liver lymphocytes were analyzed by flow cytometry. The AKT/Stat3/FOXO1 pathway was verified by targeting AKT with GSK2141795. The role of FOXO1 in liver inflammation and changes in lymphocyte phenotype was confirmed by upregulating FOXO1 with resveratrol.

RESULTS

Prolonged ischemic time aggravates liver injury in both humans and mouse models of hepatic IRI. IR-stress caused Th17/Treg imbalance and FOXO1 down-regulation by activating the AKT/Stat3/FOXO1 signaling pathway. Upregulation of FOXO1 reversed the Th17/Treg cytokine imbalance and altered the inflammation environment in the liver.

CONCLUSIONS

Liver IRI induced Th17/Treg imbalance. Upregulation of FOXO1 reversed the imbalance and alleviated liver inflammation.

摘要

背景与目的

手术过程中发生的肝脏缺血再灌注损伤（IRI）严重影响患者预后。IRI的具体机制尚未完全阐明。本研究旨在探讨肝脏IRI中炎症环境的变化，以及Th17/Treg细胞比值与FOXO1表达之间的关系。

方法

收集患者和小鼠在不同缺血时间的肝脏样本。通过蛋白质免疫印迹法和定量聚合酶链反应检测肝脏中炎症标志物和FOXO1的表达。采用流式细胞术分析肝脏淋巴细胞的表型变化。用GSK2141795靶向AKT验证AKT/Stat3/FOXO1信号通路。用白藜芦醇上调FOXO1，证实FOXO1在肝脏炎症中的作用及淋巴细胞表型的变化。

结果

在人类和小鼠肝脏IRI模型中，缺血时间延长均会加重肝损伤。缺血应激通过激活AKT/Stat3/FOXO1信号通路导致Th17/Treg失衡和FOXO1下调。上调FOXO1可逆转Th17/Treg细胞因子失衡，并改变肝脏中的炎症环境。

结论

肝脏IRI诱导Th17/Treg失衡。上调FOXO1可逆转这种失衡并减轻肝脏炎症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/b0ad31f2d957/JCTH-10-1138-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/96f5fe12f1d8/JCTH-10-1138-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/bb9d9b08ca69/JCTH-10-1138-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/2f77d8f3b25a/JCTH-10-1138-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/01cb1b0d8f09/JCTH-10-1138-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/0d5080264451/JCTH-10-1138-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/b0ad31f2d957/JCTH-10-1138-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/96f5fe12f1d8/JCTH-10-1138-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/bb9d9b08ca69/JCTH-10-1138-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/2f77d8f3b25a/JCTH-10-1138-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/01cb1b0d8f09/JCTH-10-1138-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/0d5080264451/JCTH-10-1138-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aea/9634774/b0ad31f2d957/JCTH-10-1138-g006.jpg

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