Innate immune signaling in alcoholic liver disease

酒精性肝病中的先天免疫信号

基本信息

批准号：
10092047
负责人：
Gyongyi Szabo
金额：
$ 39.38万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092047
关键词：
Acute Acute Alcoholic Hepatitis Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Apoptosis Attenuated BH3 Domain Biological Bone Marrow Cells Characteristics Chronic Clinical Cyclic GMP DNA Data Disease Endoplasmic Reticulum Event Future Gene Activation Hepatocyte Human IRF3 gene Immune Immune signaling In Vitro Inflammasome Inflammation Interferons Intervention Knowledge Leaky Gut Ligands Liver Mediating Mitochondria Mitochondrial DNA Mononuclear Mus Pathology Pathway interactions Patients Pharmacology Phosphorylation Play Preclinical Testing Production Reporting Research Role Severities Severity of illness Signal Pathway Signal Transduction Signaling Molecule Specificity Sterility Stimulator of Interferon Genes TLR4 gene Testing Therapeutic adenylate kinase alcohol effect base cell injury chronic alcohol ingestion chronic liver disease design ds-DNA effective therapy endoplasmic reticulum stress experimental study gene therapy in vivo liver injury macrophage monocyte mouse model new therapeutic target novel novel therapeutics pre-clinical promoter sensor siRNA delivery therapeutic evaluation

项目摘要

Abstract Alcoholic liver disease (ALD) and its clinically most devastating presentation, alcoholic hepatitis, is a result of cumulative biological events such as leaky gut, hepatocyte damage and inflammation that collectively contribute to the severity of liver damage. Our studies delineated a unique role for interferon regulatory factor 3 (IRF3) in alcohol-related inflammation and hepatocyte damage. We reported that the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING), is required for IRF3 phosphorylation and that IRF3 induces mitochondrial apoptosis in hepatocytes. Preliminary data shows that both alcohol binge or chronic alcohol increase circulating bacterial 16S DNA and mitochondrial DNA levels in mice and humans. These double stranded DNAs are ligands for the cyclic GMP-AMP kinase (cGAS) that produces 2′3′-cGAMP (cGAMP) that can activate STING to trigger IRF3 activation and Type I IFN production. We postulate that STING activation is at the crossroads of alcohol-induced liver pathology and in addition to ER stress, STING is also activated via cGAS-cGAMP in ALD. We further hypothesize that cGAS-mediated signals and STING activation represent a trigger for an acute-on-chronic alcohol-induced liver injury often seen in acute alcoholic hepatitis. We proposee that the cGAS-cGAMP-STING activation axis plays a role both in hepatocytes and immune cells in alcoholic hepatitis. We also discovered that sterile danger signals released by damaged hepatocytes activate the NLRP3 inflammasome in immune cells and that disruption of inflammasome activation pathways can ameliorate ALD in mice. We propose that inflammasome activation and ER stress are bi-directionally regulated in ALD. Our Aims are: 1. To investigate the role of the DNA sensor, cGAS, and dsDNA in STING-IRF3 activation in ALD; 2. To delineate the cell-specificity of cGAS and STING activation in ALD in hepatocytes and innate immune cells; 3. To investigate interactions between ER stress, inflammasome activation and STING-IRF3 activation in ALD; 4. To investigate the biological effect and therapeutic benefit of cGAS and STING inhibition on liver damage, steatosis and inflammation in ALD. These experiments will test novel roles of the cGAS-STING innate immune signaling pathways in ALD and identify key signaling molecules, for designing new therapies for ALD.

抽象的酒精性肝病（ALD）及其临床上最具破坏性的表现，酒精性肝炎是由累积的生物学事件，例如肠道渗漏，肝细胞损伤和炎症对肝脏损害严重程度的贡献。我们的研究描述了干扰素调节因子3的独特作用（IRF3）与酒精相关的炎症和肝细胞损伤中。我们报告说内质网（ER）辅助器，干扰素基因的刺激剂（sting），是IRF3磷酸化所必需的，而IRF3则需要在肝细胞中诱导线粒体凋亡。初步数据表明，酒精暴饮或慢性酒精会增加小鼠和人类中循环细菌16S DNA和线粒体DNA水平。这些双链DNA是产生2'3'-cgamp的环状GMP-AMP激酶（CGA）的配体（CGAMP）可以激活STING以触发IRF3激活和I型IFN产生。我们假设刺激激活是酒精诱导的肝脏病理学的十字路口，除了ER应力外，sting是也通过ALD中的CGAS-CGAMP激活。我们进一步假设CGAS介导的信号和刺激激活代表了急性酒精诱发的肝损伤的触发因素，经常在急性酒精中看到肝炎。我们建议CGAS-CGAMP-sting激活轴在肝细胞和酒精性肝炎中的免疫细胞。我们还发现，被损坏的无菌危险信号肝细胞激活免疫细胞中的NLRP3炎症体，并破坏炎症体激活途径可以改善小鼠的ALD。我们建议炎性体激活和ER应力是双向调节ALD。我们的目标是：1。研究DNA传感器，CGA和 dsDNA在ALD中的sting-irf3激活中； 2。描绘CGA的细胞特异性和刺激激活肝细胞和先天免疫菌株的ALD； 3。研究ER应力之间的相互作用，炎症体 ALD中的激活和刺激性IRF3激活； 4。研究生物学效应和治疗益处 CGA和对ALD中肝损伤，脂肪变性和炎症的刺激。这些实验将测试 CGAS刺激先天免疫信号通路的新作用ALD并识别关键信号传导分子，用于为ALD设计新疗法。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Review article: vascular effects of PPARs in the context of NASH.

DOI：
10.1111/apt.17046
发表时间：
2022-07
期刊：
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
影响因子：
7.6
作者：
Guixe-Muntet, Sergi;Biquard, Louise;Szabo, Gyongyi;Dufour, Jean-Francois;Tacke, Frank;Francque, Sven;Rautou, Pierre-Emmanuel;Gracia-Sancho, Jordi
通讯作者：
Gracia-Sancho, Jordi

Molecular hepatic carcinogenesis: impact of inflammation.

DOI：
10.1159/000336913
发表时间：
2012
期刊：
Digestive diseases (Basel, Switzerland)
影响因子：
0
作者：
Szabo G;Lippai D
通讯作者：
Lippai D

Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice.

DOI：
10.1111/acer.13096
发表时间：
2016-07
期刊：
Alcoholism, clinical and experimental research
影响因子：
0
作者：
Bukong TN;Iracheta-Vellve A;Gyongyosi B;Ambade A;Catalano D;Kodys K;Szabo G
通讯作者：
Szabo G

Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice.

DOI：
10.1111/liv.13430
发表时间：
2017-07
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
0
作者：
Iracheta-Vellve A;Petrasek J;Gyogyosi B;Bala S;Csak T;Kodys K;Szabo G
通讯作者：
Szabo G

FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.