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Gut extracellular vesicles promote alcohol-induced liver injury via TLR4-regulated miRNAs

肠道细胞外囊泡通过 TLR4 调节的 miRNA 促进酒精引起的肝损伤

基本信息

批准号：
9753076
负责人：
Zhong-Bin Deng
金额：
$ 18.29万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753076
关键词：
Address Affect Alcoholic Liver Diseases Alcohols Antigens Attenuated Automobile Driving Cell physiology Cells Chronic Colitis Colon Carcinoma Data Development Diet Distant Epithelial Epithelial Cells Event Foundations Future Goals Hepatic Hepatocyte Hypoxia Immune Immune signaling Immunotherapy Impairment In Vitro Inflammation Inflammatory Inflammatory disease of the intestine Injury Intervention Intestinal permeability Intestines Investigation Kupffer Cells Lead Link Liver Liver diseases Macrophage Activation Mediating MicroRNAs Molecular Myeloid Cells Outcome Pathogenicity Patients Play Preventive Production Proteins Publishing Regulation Role Severities Signal Transduction TLR4 gene Testing Therapeutic Tumor Angiogenesis Ulcerative Colitis Work antimicrobial base chronic alcohol ingestion exosome extracellular extracellular vesicles gut microbiota gut-liver axis immunoregulation improved in vivo inhibitor/antagonist interest liver development liver inflammation liver injury macrophage microbial microorganism antigen migration mouse model nanoparticle nanovesicle novel nutrition overexpression prevent recruit response therapeutic target translational study vesicular release

项目摘要

The overarching theme of this project is to explore the mechanisms that lead to immune regulation of alcoholic liver disease (ALD). We will focus on extracellular vesicles (EVs) of gut and hepatic macrophages. Specifically, we will examine how microbial antigen stimulates the production of gut EVs through TLR4 signaling and the consequences of these events in the development of ALD via gut-liver axis. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that gut-derived EVs regulate the accumulation and polarization of hepatic macrophages during alcohol-induced chronic inflammation via TLR4 signaling. We specifically propose that TLR4-activated extracelluar miRNAs production is the key to the activation of macrophages. Based on our published work and other preliminary data, this proposal will test the hypothesis that microbial antigen regulates the production of gut extracellular miRNAs through TLR4 signaling, which initiates a crosstalk among macrophages and hepatocytes in ALD. Moreover, we will determine whether diet-associated nanoparticles carrying inflammatory miRNAs inhibitor have potential therapeutic implications in ALD. These hypotheses will be tested in the following Specific Aims: Aim 1: Determine the role of TLR4-regulated gut EVs on alcohol-induced liver inflammation and injury. Aim 2: Determine whether alteration of IEC miRNAs via TLR4 modulation affects the severity of alcohol-induced liver inflammation and injury in ALD. Following the successful completion of the above Specific Aims, our novel studies will (i) validate TLR4 activated EVs is directly relevant to the activation of hepatic macrophages in ALD, (ii) define the preventive potential of TLR4-extracellular miRNAs axis in a mouse model of ALD and (iii) provide a foundation for future mechanistic investigation of gut EVs and extracellular miRNA in ALD therapy.

该项目的首要主题是探索导致酒精免疫调节的机制肝病（ALD）。我们将重点关注肠道和肝巨噬细胞的细胞外囊泡（EV）。具体来说，我们将研究微生物抗原如何通过 TLR4 信号传导刺激肠道 EV 的产生以及这些事件通过肠-肝轴发展为 ALD 的后果。新颖的体外和体内方法将用于解决行动机制问题，以期确定新的干预目标。我们提出肠道来源的 EVs 调节肝巨噬细胞的积累和极化酒精通过 TLR4 信号传导诱导慢性炎症。我们特别建议 TLR4 激活细胞外miRNA的产生是巨噬细胞激活的关键。基于我们已发表的作品和其他初步数据，该提案将检验微生物抗原调节生产的假设通过 TLR4 信号传导肠道细胞外 miRNA，从而启动巨噬细胞和 ALD 中的肝细胞。此外，我们将确定饮食相关的纳米颗粒是否携带炎症 miRNA 抑制剂对 ALD 具有潜在的治疗意义。这些假设将在下面进行检验具体目标：目标 1：确定 TLR4 调节的肠道 EV 对酒精诱导的肝脏炎症的作用和伤害。目标 2：确定通过 TLR4 调节改变 IEC miRNA 是否会影响严重程度 ALD 中酒精引起的肝脏炎症和损伤。顺利完成以上工作后具体目标是，我们的新研究将 (i) 验证 TLR4 激活的 EV 与肝细胞的激活直接相关 ALD 中的巨噬细胞，(ii) 定义了 TLR4-细胞外 miRNA 轴在小鼠模型中的预防潜力 ALD 和 (iii) 为未来 ALD 中肠道 EV 和细胞外 miRNA 的机制研究奠定了基础治疗。