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：
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
项目类别：
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

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.

项目概要/摘要由于潜在肝病激增，酒精相关性肝病 (ALD) 导致的死亡人数不断增加饮酒量增加。 ALD 是一个术语，用于描述一系列严重程度不等的疾病。患有包括纤维化在内的晚期疾病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到进行性疾病的转变。因此，临床上迫切需要了解触发 ALD 患者纤维化的分子机制有助于开发有效的治疗方法遏制 ALD 进展并提高生存率的策略。这需要了解免疫细胞负责调节肝损伤和修复之间动态相互作用的介质。干扰素监管因子 3 (IRF3) 是一种诱导抗病毒基因的转录因子，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 (DRBP) RIG-I 和 IRF3 可以与 IKKb 相互作用，阻止炎症的 NFkB 转录细胞因子。乙醇诱导的肝细胞应激导致 dsRNA 生成增加，引发下游炎症细胞因子的产生。 dsRNA 源自病毒复制或宿主来源它作为损伤相关分子模式 (DAMP) 发挥作用，发出损伤信号（传统上来自病毒感染）。目前，在没有病毒感染的情况下，dsRNA 积累的研究最多的来源起源于线粒体，与异常的 dsRNA 降解途径相关。在上下文中对于 ALD，我们预测 dsRNA 会导致过度的免疫反应，从而恶化生命损伤，纤维化。这可能是通过 dsRNA 诱导的 IRF3 激活介导的。我们的实验室证明 Irf3-/- 小鼠免受乙醇诱导的肝损伤，而仅表达 IRF3 非转录功能的小鼠不受保护。 Irf3 的这种非转录效应是由 IRF3 介导的特定细胞凋亡驱动的。浸润性单核细胞群导致肝脏炎症恶化并导致乙醇- 对小鼠造成损伤。该提案的初步数据表明，在慢性 CCl4 纤维化损伤中模型中，Irf3-/- 小鼠的纤维化损伤较少，中性粒细胞（一种先天免疫细胞）的浸润增加最近涉及保护免受伤害的人群。因此，由于 IRF3 调节单核细胞表型并增加中性粒细胞浸润，并且 dsRNA 可以通过 IRF3 触发 ALD 中的免疫反应，我们假设乙醇会增加 dsRNA 诱导的 IRF3 激活，从而导致中性粒细胞浸润并增加纤维化与 ALD 相关的肝损伤。在本提案中，我们将确定体内 IRF3 激活如何增强肝脏功能酒精加速纤维化模型中的损伤并表征体内敲除模型 dsRNA 传感对乙醇的反应。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。完成这些研究将有助于更好地了解先天免疫系统和 ALD 相关纤维化之间的相互作用。