IRF3 activation promotes fibrotic liver injury in alcohol-associated-liver disease

IRF3 激活促进酒精相关性肝病中的纤维化肝损伤

基本信息

批准号：
10666436
负责人：
Christina Katherine Du Ross
金额：
$ 5.57万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2024-04-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666436
关键词：
Acceleration Acute Alcohol consumption Alcohol-Induced Disorders Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Anti-Inflammatory Agents Antibodies Apoptosis Apoptotic Benign Binding Proteins Biological Assay Cells Chronic Cirrhosis Clinical Data Degradation Pathway Developed Countries Development Disease Disease Progression Double-Stranded RNA Enzymes Ethanol Fibrosis Generations Genetic Transcription Genotype Hepatitis Hepatocyte IRF3 gene Immune Immune response Infiltration Inflammatory Injury Innate Immune Response Innate Immune System Interferon-beta Knock-out Life Expectancy Liver Liver Fibrosis Liver diseases Liver parenchyma Mediating Mediator Mitochondria Modeling Molecular Mus NF-kappa B Neutrophil Infiltration Nuclear Pore Complex Outcome Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Phenotype Phosphorylation Play Population Predisposition Production Progressive Disease Reporting Resolution Role Severities Signal Transduction Source Stress United States Viral Viral Genes Virus Diseases Virus Replication acetaminophen-induced liver injury advanced disease alcohol abuse therapy alcohol response alcohol-related death biomarker identification chemokine chronic liver injury cytokine disease classification drug development effective therapy fibrogenesis hepatocyte injury immune cell infiltrate improved in vivo liver inflammation liver injury liver repair monocyte neutrophil prevent recruit response severe injury transcription factor treatment strategy

项目摘要

Project Summary/ Abstract Deaths from alcohol-related liver disease (ALD) are increasing due to a surge in underlying liver disease and increased alcohol consumption. ALD is a term used to describe a spectrum of diseases that range in severity. Patients with advanced disease, including fibrosis have few treatment options. Fibrosis is a disease stage indicative of transition from benign to progressive disease. Therefore, there is a clinical urgency to understand the molecular mechanism triggering fibrosis in patients with ALD to aid in the development of effective treatments strategies to curb ALD progression and improve survival. This requires an understanding of immune cell mediators responsible for modulating the dynamic interplay between liver injury and repair. Interferon regulatory factor 3 (IRF3) is a transcription factor that induces antiviral genes and is implicated in the progression of ALD. IRF3 also has non-transcriptional function involving a pro-apoptotic pathway mediated by the dsRNA binding protein (DRBP) RIG-I and IRF3 which can interact with IKKb to prevent NFkB transcription of inflammatory cytokines. Ethanol-induced stress in hepatocytes results in increased generation of dsRNA, triggering downstream inflammatory cytokine production. dsRNA originates from viral replication or host-derived sources and it functions as a damage associated molecular pattern (DAMP) to signal injury (traditionally from viral infection). Currently, the most investigated source of dsRNA accumulation in the absence of viral infection originates from the mitochondria and is associated with aberrant dsRNA degradation pathways. In the context of ALD, we predicted that dsRNA contributes to an exaggerated immune response worsening living injury and fibrosis. This may be mediated via dsRNA-induced IRF3 activation. Our lab demonstrated that Irf3-/- mice were protected from ethanol-induced liver injury, while mice expressing only non-transcriptional function of IRF3 were not protected. This non-transcriptional effect of Irf3 was driven by IRF3-mediated apoptosis of specific populations of infiltrating monocytes that resulted in worsened hepatic inflammation and contributed to ethanol- induced injury in mice. Preliminary data from this proposal demonstrates that in a chronic CCl4 fibrosis injury model, Irf3-/- mice have less fibrotic injury and increased infiltration of neutrophils, an innate immune cell population recently implicated in protection from injury. Therefore, since IRF3 modulates monocyte phenotype and increases neutrophil infiltration and dsRNA can trigger immune responses in ALD via IRF3, we hypothesize that ethanol increases dsRNA-induced IRF3 activation contributing to neutrophil infiltration and increased fibrotic liver injury associated with ALD. In this proposal, we will determine how IRF3 activation in vivo increases liver injury in an alcohol-accelerated fibrosis model and characterize in vivo knockout models dsRNA sensing response to ethanol. We will also determine the role of IRF3 in modulating neutrophil infiltration and phenotype in an alcohol-accelerated fibrosis model. Completion of these studies will contribute towards a better understanding of the crosstalk between the innate immune system and ALD-associated fibrosis.

项目摘要/摘要由于肝病的潜在疾病激增和饮酒量增加。 ALD是一个用于描述严重程度范围的疾病范围的术语。患有晚期疾病的患者（包括纤维化）几乎没有治疗选择。纤维化是疾病阶段指示从良性到进行性疾病的过渡。因此，有一个临床紧迫的理解触发ALD患者纤维化的分子机制有助于开发有效治疗遏制ALD进展并改善生存的策略。这需要了解免疫细胞负责调节肝损伤与修复之间的动态相互作用的介体。干扰素调节因子3（IRF3）是诱导抗病毒基因的转录因子，并与ALD的进展有关。 IRF3还具有非转录功能，涉及由DSRNA结合介导的促凋亡途径蛋白质（DRBP）RIG-1和IRF3可以与IKKB相互作用以防止NFKB炎症转录细胞因子。乙醇诱导的肝细胞应激会导致DSRNA的产生增加，从而触发下游炎症细胞因子产生。 DSRNA起源于病毒复制或宿主衍生的来源它起着损害相关的分子模式（潮湿）的作用（传统上是病毒损伤）感染）。目前，在没有病毒感染的情况下，最多研究的DSRNA积累来源起源于线粒体，与异常的DSRNA降解途径有关。在上下文中在ALD中，我们预测DSRNA有助于夸张的免疫反应，使生活受伤恶化和纤维化。这可以通过DSRNA诱导的IRF3激活介导。我们的实验室证明IRF3 - / - 小鼠是免受乙醇诱导的肝损伤的保护，而仅表达IRF3非转录功能的小鼠是不受保护。 IRF3的这种非转录作用是由IRF3介导的特定凋亡驱动的浸润的单核细胞群体导致肝发炎恶化，并导致乙醇小鼠诱发损伤。该提案的初步数据表明，在慢性CCL4纤维化损伤中模型，IRF3 - / - 小鼠的纤维化损伤较少，中性粒细胞浸润增加，先天免疫细胞最近的人口涉及保护免受伤害。因此，由于IRF3调节单核细胞表型并增加中性粒细胞浸润和dsRNA可以通过IRF3触发ALD的免疫反应，我们假设乙醇增加了DSRNA诱导的IRF3激活，导致嗜中性粒细胞浸润并增加纤维化与ALD相关的肝损伤。在此提案中，我们将确定IRF3在体内如何增加肝脏酒精加速纤维化模型的损伤，并在体内敲除模型中表征DSRNA感应对乙醇的反应。我们还将确定IRF3在调节中性粒细胞浸润和表型中的作用在酒精加速纤维化模型中。这些研究的完成将有助于更好了解先天免疫系统与ALD相关纤维化之间的串扰。