Alcohol and Monocyte Signaling

酒精和单核细胞信号传导

基本信息

批准号：
9889864
负责人：
Gyongyi Szabo
金额：
$ 39.38万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889864
关键词：
Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic liver damage Alcohols Anti-Inflammatory Agents Apoptosis Apoptotic Attenuated Blood Circulation Cell Communication Cells Characteristics Chronic Data Fatty Liver Fibrosis Hepatocyte Human Immune Immune response Immune system In Vitro Inflammation Inflammatory Intervention Kupffer Cells Liver Macrophage Activation Mediating Membrane MicroRNAs Mus Neutrophil Infiltration Organ Organelles Outcome Pathogenesis Patients Phagocytes Phagocytosis Phenotype Play Population Reporting Role Signal Transduction Testing Therapeutic Therapeutic Effect Therapeutic Intervention Vesicle alcohol effect alcohol exposure base binge drinking cell type chronic alcohol ingestion cytokine experimental study extracellular vesicles in vivo insight intercellular communication liver inflammation liver injury macrophage monocyte mouse model neutrophil novel novel therapeutics pre-clinical problem drinker public health relevance recruit therapeutic target tissue repair transcription factor

项目摘要

DESCRIPTION (provided by applicant) Macrophages (MØ), Kupffer cells (KC) and neutrophils mediate inflammation in the pathogenesis of alcoholic liver disease (ALD). Previous studies have demonstrated damaging effects of pro-inflammatory macrophages on alcoholic liver inflammation and high neutrophil infiltration in the liver predicted poor outcome in human alcoholic hepatitis. Prior reports in humans and our preliminary data in mice show that both classically activated inflammatory, M1, and alternatively activated, M2, macrophages are present in the liver after chronic alcohol intake. However, the significance of M1 and M2 type macrophage (MØ) polarization or therapeutic targeting of MØ polarization is yet to be explored in ALD. We hypothesize that insufficient M2 polarization permits chronic inflammation and preferential M1 macrophage phenotype in the liver. We further hypothesize that reduced M2 MØ polarization is due, at least partially, to insufficient phagocytosis of neutrophils. We postulate that therapeutic interventions that promote M2 macrophage polarization will attenuate alcohol- induced liver inflammation and injury. We recently found that MØ polarizing microRNAs are also packaged in extracellular vesicles (EVs), small membrane vesicles that could act as signaling organelles in cell-to-cell communication. In our preliminary experiments, we observed that the number of EVs is increased in the circulation of humans and mice with alcoholic liver injury. We hypothesize that alcohol-induced EVs are important regulators of inflammation and macrophage polarization in the liver. Based on these observations, our aims are: Specific Aim#1: To investigate the role of alcohol-induced extracellular vesicles (EVs) on macrophage activation and polarization by a) evaluating the effects of in vivo alcohol-induced EVs on macrophage polarization in vitro; b) testing the effect of in vivo alcohol-induced EVs on recruitment and phenotype of inflammatory cells in the liver in vivo; c) testing the effect of hepatocyte-derived EVs and their characteristic miRNAs on macrophage polarization in vitro; d) evaluating circulating EVs in human patients with alcoholic hepatitis, characterizing their miRNA composition and effect on monocyte polarization. Specific Aim#2: To investigate triggers of macrophage polarization in ALD by evaluating modulation of neutrophils by alcohol and their role in M1/M2 macrophage polarization in vitro and in vivo in patients with alcoholic hepatitis. Specific Aim#3: To explore the therapeutic potential of interventions that modulate MØ phenotype/polarization on alcohol-induced liver steatosis, inflammation and liver damage in mice.

描述（由申请人提供）巨噬细胞（MØ）、库普弗细胞（KC）和中性粒细胞在酒精性肝病（ALD）的发病机制中介导炎症。先前的研究已经证明促炎性巨噬细胞对酒精性肝炎症和高中性粒细胞浸润具有破坏性作用。先前在人类中的报告和我们在小鼠中的初步数据表明，肝脏中的炎症因子 M1 和 M1 均被激活。长期饮酒后，肝脏中存在替代激活的 M2 巨噬细胞。然而，M1 和 M2 型巨噬细胞 (MØ) 极化或 MØ 极化的治疗靶向的重要性尚未在 ALD 中探索。我们进一步发现，M2 MØ极化的减少至少部分是由于中性粒细胞的吞噬作用不足。假设促进 M2 巨噬细胞极化的治疗干预措施将减轻酒精引起的肝脏炎症和损伤，我们最近发现 MØ 极化 microRNA 也包装在细胞外囊泡 (EV) 中，这种小膜囊泡可以充当细胞间的信号细胞器。在我们的初步实验中，我们观察到酒精性肝损伤的人和小鼠的循环中 EV 数量增加，我们发现酒精诱导的 EV 很重要。基于这些观察，我们的目标是：具体目标#1：通过 a) 评估酒精诱导的细胞外囊泡 (EV) 对巨噬细胞活化和极化的作用。体内酒精诱导的 EV 对体外巨噬细胞极化的影响；b) 测试体内酒精诱导的 EV 对体内肝脏炎症细胞的募集和表型的影响；c) 测试肝细胞来源的 EV 的影响； EV 及其特征 miRNA 在体外对巨噬细胞极化的影响；d) 评估酒精性肝炎患者的循环 EV，表征其 miRNA 组成及其对单核细胞极化的影响。具体目标#2：通过评估 ALD 中巨噬细胞极化的触发因素。酒精对中性粒细胞的影响及其在酒精性肝炎患者体内和体外 M1/M2 巨噬细胞极化中的作用：探索治疗方法。调节 MØ 表型/极化的干预措施对酒精诱导的小鼠肝脏脂肪变性、炎症和肝损伤的潜力。

项目成果

期刊论文数量（41）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bone marrow-derived immune cells mediate sensitization to liver injury in a myeloid differentiation factor 88-dependent fashion.

骨髓源性免疫细胞以骨髓分化因子 88 依赖性方式介导对肝损伤的敏感性。

DOI：
发表时间：
2008-10
期刊：
影响因子：
0
作者：
Hritz, Istvan;Velayudham, Arumugam;Dolganiuc, Angela;Kodys, Karen;Mandrekar, Pranoti;Kurt;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi

Gut-liver axis and sensing microbes.

肠肝轴和传感微生物。

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Szabo, Gyongyi;Bala, Shashi;Petrasek, Jan;Gattu, Arijeet
通讯作者：
Gattu, Arijeet

Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90.

患有酒精性肝病的小鼠的细胞外囊泡携带独特的蛋白质货物，并通过热休克蛋白 90 诱导巨噬细胞活化。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Saha, Banishree;Momen;Furi, Istvan;Kodys, Karen;Catalano, Donna;Gangopadhyay, Anwesha;Haraszti, Reka;Satishchandran, Abhishek;Iracheta;Adejumo, Adeyinka;Shaffer, Scott A;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi

Gut-Liver Axis Beyond the Microbiome: How the Fungal Mycobiome Contributes to Alcoholic Liver Disease.

微生物组之外的肠道-肝脏轴：真菌真菌组如何导致酒精性肝病。