Innate immune signaling in alcoholic liver disease

酒精性肝病中的先天免疫信号

• 批准号: 10022027
• 负责人: Gyongyi Szabo
• 金额: $ 24.06万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022027
• 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; Small Interfering RNA; 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; therapeutic evaluation

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.

摘要 酒精性肝病（ALD）及其临床上最具破坏性的表现，酒精性肝炎，是由于 累积的生物学事件，如肠漏、肝细胞损伤和炎症， 导致肝损伤的严重程度我们的研究描绘了干扰素调节因子3的独特作用 （IRF 3）在酒精相关炎症和肝细胞损伤中的作用。我们报道过内质网 (ER)衔接子，干扰素基因刺激因子（STING），是IRF 3磷酸化所必需的，IRF 3 诱导肝细胞线粒体凋亡。初步数据显示，酗酒或慢性 酒精增加循环细菌16 S DNA和线粒体DNA水平在小鼠和人类。这些 双链DNA是产生2′3′-cGAMP的环GMP-AMP激酶（cGAS）的配体 （cGAMP）可以激活STING以触发IRF 3激活和I型IFN产生。我们推测 STING激活处于酒精诱导的肝脏病理学的十字路口，并且除了ER应激之外，STING还 在ALD中也通过cGAS-cGAMP激活。我们进一步假设cGAS介导的信号和STING 激活代表了急性慢性酒精性肝损伤的触发因素， 肝炎我们认为cGAS-cGAMP-STING激活轴在肝细胞和肝细胞中起作用， 酒精性肝炎中的免疫细胞我们还发现，受损的植物释放的无菌危险信号 肝细胞激活免疫细胞中NLRP 3炎性体， 激活途径可以改善小鼠的ALD。我们认为炎性小体激活和内质网应激是 在ALD中双向调节。我们的目标是：1。为了研究DNA传感器cGAS的作用， ALD中STING-IRF 3激活中的dsDNA; 2.为了描述cGAS和STING激活的细胞特异性， 肝细胞和先天免疫细胞中的ALD; 3.研究内质网应激、炎性小体、 ALD中的STING-IRF 3激活和STING-IRF 3激活; 4.目的：探讨生物学效应和治疗效果， cGAS和STING抑制ALD中的肝损伤、脂肪变性和炎症。这些实验将测试 cGAS-STING先天免疫信号通路在ALD中的新作用，并确定关键信号通路 分子，用于设计ALD的新疗法。