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.

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 累积的生物事件，如肠漏、肝细胞损伤和炎症，这些事件共同作用 我们的研究揭示了干扰素调节因子 3 的独特作用。 我们报道了IRF3在酒精相关炎症和肝细胞损伤中的作用。 (ER) 接头，干扰素基因 (STING) 的刺激物，是 IRF3 磷酸化所必需的，并且 IRF3 初步数据显示，无论是酗酒还是慢性饮酒，都会诱导肝细胞线粒体凋亡。 酒精会增加小鼠和人类体内循环细菌 16S DNA 和线粒体 DNA 的水平。 双链 DNA 是环 GMP-AMP 激酶 (cGAS) 的配体，可产生 2'3'-cGAMP (cGAMP) 可以激活 STING 以触发 IRF3 激活和 I 型 IFN 产生。 STING 激活处于酒精引起的肝脏病理学的十字路口，除了 ER 应激之外，STING 还 我们还通过 ALD 中的 cGAS-cGAMP 激活了 cGAS 介导的信号和 STING。 激活代表慢性酒精急性肝损伤的触发因素，常见于急性酒精中毒 我们认为 cGAS-cGAMP-STING 激活轴在肝细胞和肝炎中都发挥作用。 我们还发现酒精性肝炎中的免疫细胞受损时会释放出无菌的危险信号。 肝细胞激活免疫细胞中的 NLRP3 炎症小体并破坏炎症小体 我们认为炎症小体激活和内质网应激是改善小鼠 ALD 的机制。 我们的目标是： 1. 研究 DNA 传感器、cGAS 和 DNA 传感器的作用。 ALD 中 STING-IRF3 激活中的 dsDNA 2. 描述 cGAS 和 STING 激活的细胞特异性； 3. 肝细胞和先天免疫细胞中的ALD；研究ER应激、炎症小体之间的相互作用； 4. 研究ALD中STING-IRF3的激活和治疗益处； 这些实验将测试 cGAS 和 STING 对 ALD 中肝损伤、脂肪变性和炎症的抑制作用。 cGAS-STING 先天免疫信号通路在 ALD 中的新作用并确定关键信号传导 分子，用于设计 ALD 新疗法。