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

• 批准号: 10312227
• 负责人: Christina Katherine Du Ross
• 金额: $ 6.64万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2024-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312227
• 关键词: Acceleration; Acetaminophen; Acute; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Anti-Inflammatory Agents; Antibodies; Antiviral Agents; Apoptosis; Apoptotic; Attenuated; Benign; Binding Proteins; Biological Assay; Cells; Chronic; Clinical; Data; Degradation Pathway; Developed Countries; Development; Disease; Disease Progression; Double-Stranded RNA; Enzymes; Ethanol; Fibrosis; Generations; Genes; Genetic Transcription; Genotype; Hepatic; Hepatitis; Hepatocyte; IRF1 gene; IRF3 gene; Immune; Immune response; Inflammation; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Interferon Regulatory Factor 2; Interferon-beta; Knock-out; Life Expectancy; Liver; Liver Fibrosis; Liver diseases; Liver parenchyma; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Mus; Neutrophil Infiltration; Nuclear Pore Complex; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Play; Population; Predisposition; Production; Progressive Disease; Reporting; Resolution; Role; Severities; Signal Transduction; Source; Stress; Tumor-infiltrating immune cells; United States; Viral; Virus Diseases; Virus Replication; advanced disease; alcohol abuse therapy; alcohol response; alcohol-related death; chemokine; chronic liver injury; cytokine; drug development; effective therapy; fibrogenesis; hepatocyte injury; improved; in vivo; injury and repair; liver injury; monocyte; neutrophil; prevent; recruit; response; severe injury; transcription factor; treatment strategy

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.

项目总结/摘要 由于基础肝病的激增，酒精相关肝病（ALD）的死亡人数正在增加， 增加酒精消费。ALD是一个术语，用于描述一系列严重程度不等的疾病。 患有晚期疾病（包括纤维化）的患者几乎没有治疗选择。纤维化是疾病的一个阶段 表明从良性疾病转变为进行性疾病。因此，有一个临床迫切需要了解 触发ALD患者纤维化的分子机制，以帮助开发有效的治疗方法 抑制ALD进展和提高生存率的策略。这需要了解免疫细胞 负责调节肝损伤和修复之间的动态相互作用的介质。干扰素调节 因子3（IRF 3）是诱导抗病毒基因的转录因子，并且与ALD的进展有关。 IRF 3还具有涉及由dsRNA结合介导的促凋亡途径的非转录功能， RIG-I和IRF 3可以与IKKb相互作用，阻止炎症因子NF κ B的转录。 细胞因子乙醇诱导的肝细胞应激导致dsRNA的产生增加，从而触发 下游炎症细胞因子的产生。dsRNA来源于病毒复制或宿主来源 并且其作为损伤相关分子模式（DAMP）对信号损伤（传统上来自病毒）起作用， 感染）。目前，在没有病毒感染的情况下，研究最多的dsRNA积累来源是 来源于线粒体，与异常dsRNA降解途径相关。背景下 对于ALD，我们预测dsRNA有助于夸大的免疫反应，使活体损伤恶化， 纤维化这可以通过dsRNA诱导的IRF 3活化来介导。我们的实验室证明，Irf 3-/-小鼠 保护免受乙醇诱导的肝损伤，而仅表达IRF 3非转录功能的小鼠则被 不受保护。IRF 3的这种非转录作用是由IRF 3介导的特异性细胞凋亡驱动的。 浸润的单核细胞群导致肝脏炎症恶化，并导致乙醇- 致小鼠损伤。该提案的初步数据表明，在慢性四氯化碳纤维化损伤中， 在模型中，Irf 3-/-小鼠的纤维化损伤较少，中性粒细胞（一种先天免疫细胞）浸润增加 最近受到伤害的保护。因此，由于IRF 3调节单核细胞表型， 并增加中性粒细胞浸润，dsRNA可通过IRF 3触发ALD的免疫反应，我们假设 乙醇增加dsRNA诱导的IRF 3活化，导致中性粒细胞浸润和纤维化增加， 与ALD相关的肝损伤。在这个提议中，我们将确定IRF 3在体内的激活如何增加肝脏的 酒精加速纤维化模型中损伤和体内敲除模型中表征dsRNA传感 乙醇的反应。我们还将确定IRF 3在调节中性粒细胞浸润和表型中的作用。 酒精加速的纤维化模型。完成这些研究将有助于更好地 了解先天免疫系统和ALD相关纤维化之间的串扰。