Transcriptional and non-transcriptional functions of IRF3 in ALD

IRF3 在 ALD 中的转录和非转录功能

• 批准号: 10207370
• 负责人: LAURA E. NAGY
• 金额: $ 47.99万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207370
• 关键词: Acceleration; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; BAX gene; Bax protein; Cells; Cessation of life; Chronic; Cirrhosis; Complex; DNA; Data; Development; Double-Stranded RNA; Elements; Ethanol; Exhibits; Failure; Fibrosis; Genes; Genetic Transcription; Hepatic; Hepatitis; Homeostasis; IRF3 gene; Immune; Immune response; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferons; Knock-in Mouse; Ligands; Liver; Lysine; Mediating; Mitochondria; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Population; Proteins; Regulation; Reporter; Research Personnel; Resolution; Role; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; TLR4 gene; Therapeutic Intervention; Tissues; Ubiquitination; Viral Physiology; Virus Diseases; alcohol exposure; alcohol response; cellular targeting; chronic inflammatory disease; ds-DNA; experimental study; hepatocellular injury; improved; injury and repair; liver injury; macrophage; member; microbial; migration; monocyte; mortality; mouse model; novel; prevent; pro-apoptotic protein; receptor; recruit; response; therapeutic target; transcription factor

ABSTRACT Alcohol consumption is a leading cause of preventable morbidity and mortality worldwide. Chronic alcohol abuse underlies the pathogenesis of alcoholic liver disease (ALD), encompassed by a spectrum of pathologies, ranging from steatosis, to more severe forms of liver injury, including alcoholic hepatitis (AH), fibrosis, and cirrhosis. There is a growing appreciation of a dynamic and complex role of the innate immune system in the progression of ALD, as well as the resolution of hepatocellular injury and fibrosis. The controlled and appropriate resolution of inflammation is an essential feature of the innate immune response. This dynamic interplay between injury and repair is mediated, at least in part, by the tremendous plasticity of resident tissue macrophages and infiltrating monocytes as they respond to signals within their microenvironment. Signaling via IRF3 is an important element in the dynamic regulation of pro-survival vs pro-death pathways in immune cells. While several studies have implicated IRF3 in the progression of ALD, the mechanisms by which IRF3 contributes to liver injury are not well understood. Classically, IRF3 is known as a transcription factor essential for the induction of interferon- (IFN-) and antiviral genes. Recently, members of our team discovered that, in addition to its transcriptional functions, IRF3 directly triggers a pro-apoptotic pathway, termed RIG-I- like receptors (RLR)-induced IRF-3-mediated pathway of apoptosis (RIPA) via a non-transcriptional mechanism. In IRF3-mediated apoptosis, IRF3 is activated by linear ubiquitination on two lysine residues, resulting in the interaction of IRF3 with the pro-apoptotic protein Bax. The IRF3/BAX complex then translocates to the mitochondria where it triggers apoptosis. In order to study this pathway, we have generated a novel knock-in mouse that expresses an IRF3 protein that only exhibits non-transcriptional functions. Importantly, in preliminary experiments, we discovered that IRF3-mediated apoptosis of innate immune cells recruited to the liver in response to Gao-binge ethanol exposure dynamically exacerbates inflammation and contributes to murine alcoholic hepatitis (mAH). Here we propose to investigate the mechanisms by which the non-transcriptional activity of IRF3 contributes to both hepatic inflammation and fibrosis in models of mAH and fibrosis in 2 specific aims: SA1) Determine the contribution of the non-transcriptional function of IRF3 in mediating ethanol-induced liver injury in the Gao-binge model of mAH and a murine model of acceleration of fibrosis by ethanol and SA2) Investigate the mechanisms of IRF3 activation in immune cells during mAH or fibrosis. In summary, our studies will reveal novel roles for the non-transcriptional activity of IRF3 in exacerbating innate immune responses to alcohol, as well as identify potential therapeutic targets that would prevent and/or improve the resolution of inflammation and fibrosis in patients with ALD.

摘要 饮酒是全世界可预防的发病率和死亡率的主要原因。慢性酗酒 酒精性肝病(ALD)是酒精性肝病(ALD)的基础，包括一系列的病理 从脂肪变性到更严重的肝损伤形式，包括酒精性肝炎(AH)、纤维化和肝硬变。 人们越来越认识到先天免疫系统在这一过程中所起的动态而复杂的作用 ALD的治疗，以及肝细胞损伤和纤维化的解决。可控且适当的解决方案 炎症是先天免疫反应的一个基本特征。这种伤害之间的动态相互作用 修复至少在一定程度上是由常驻组织巨噬细胞和 当单核细胞对其微环境中的信号做出反应时，它们会渗入其中。 通过IRF3的信号是支持生存和支持死亡的通路动态调节中的一个重要因素 免疫细胞。虽然一些研究表明IRF3与ALD的进展有关，但其机制 IRF3在肝脏损伤中的作用目前还不清楚。经典地说，irf3是一种转录因子。 对干扰素-(干扰素-)和抗病毒基因的诱导至关重要。最近，我们团队的成员发现 除了其转录功能外，IRF3还直接触发了一条促凋亡途径，称为RIG-I- 类受体(RLR)通过非转录途径诱导IRF-3介导的细胞凋亡途径 机制。在IRF3介导的细胞凋亡中，IRF3被两个赖氨酸残基上的线性泛素化激活， 导致IRF3与促凋亡蛋白Bax相互作用。IRF3/Bax复合体然后移位 到线粒体，在那里它会触发细胞凋亡。为了研究这一途径，我们制作了一部小说 表达一种只具有非转录功能的IRF3蛋白的敲入小鼠。 重要的是，在初步实验中，我们发现IRF3介导的先天免疫细胞的凋亡 高饮酒后肝脏应激反应动态加剧炎症和 导致小鼠酒精性肝炎(Mah)。在这里，我们建议研究 IRF3的非转录活性与肝组织炎症和纤维化的关系 2个特定目标的纤维化：SA1)确定IRF3的非转录功能在中介中的作用 酒精性肝损伤及酒精性肝纤维化的小鼠模型 乙醇和SA2)研究MAH或纤维化过程中免疫细胞IRF3激活的机制。在……里面 综上所述，我们的研究将揭示IRF3的非转录活性在加剧先天性疾病中的新作用 对酒精的免疫反应，以及确定潜在的治疗靶点，以防止和/或改善 ALD患者炎症和纤维化的消退。