Regulation of MCP-1 and chemokine receptor 2 (CCR2) in alcoholic liver disease

MCP-1 和趋化因子受体 2 (CCR2) 在酒精性肝病中的调节

• 批准号: 7661132
• 负责人: Pranoti Mandrekar
• 金额: $ 24.68万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661132
• 关键词: Address; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Biological Assay; Blood Circulation; CC chemokine receptor 2; Cells; Chemotaxis; Chronic; Cirrhosis; Data; Development; Diet; Disease; Endotoxins; Exhibits; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Future; Gene Expression; Health; Hepatic; Human; ITGAM gene; Immune; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knockout Mice; Leukocytes; Light; Link; Liver; Macrophage Activation; Mediating; Messenger RNA; Molecular; Monocyte Chemoattractant Protein-1; Mononuclear; Mus; Necrosis; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Process; Production; Proteins; Regulation; Role; Serum; Signal Pathway; Signal Transduction; Site; Source; Testing; Therapeutic Intervention; Tissues; United States; Work; alcohol exposure; beta-Chemokines; chemokine; chemokine receptor; chronic alcohol ingestion; cytokine; feeding; in vitro Assay; insight; longitudinal analysis; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; peripheral blood; prevent; public health relevance; receptor; research study; therapy development

DESCRIPTION (provided by applicant): The importance of innate immune cells in the pathophysiology of alcoholic liver injury is evident from animal models and human studies. Resident macrophages in the liver are activated by endotoxin in portal circulation to produce inflammatory cytokines. In addition to the pro-inflammatory cytokines, macrophages also produce chemokines that can contribute to alcoholic liver injury. Our preliminary studies show increased production of serum and liver tissue MCP-1 production after chronic alcohol feeding in mice. We also show that MCP-1 deficient mice exhibit significantly decreased liver injury after chronic alcohol feeding. Increased MCP-1 in the liver can promote monocyte/macrophage infiltration in the liver and contribute to inflammatory responses. Activation of monocyte/macrophages is pivotal to the development of alcoholic liver injury. We hypothesize that chronic alcohol exposure induces MCP-1 in the liver and its receptor, CCR2 on circulating monocyte/macrophages facilitating their recruitment to the liver. Altered MCP-1/CCR2 signaling could thus contribute to innate immune cell-mediated alcoholic liver injury. The objectives of the current application are to determine the role of MCP-1/CCR2 axis in alcohol-induced liver injury. Specifically, our focus will be to first perform a longitudinal analysis of MCP-1 expression in the liver and correlate these changes with alterations in resident and infiltrating macrophages in the liver after chronic alcohol feeding. Next, we will analyze the MCP-1 receptor, CCR2 on circulating monocytes after chronic alcohol feeding. We will also determine the effect of chronic alcohol on chemotaxis of CCR2-expressing monocyte/macrophages in an in vitro assay. Finally, using CCR2 knock out mice we will determine the pathophysiological significance of the MCP-1/CCR2 axis in alcohol- induced fatty liver injury. To achieve these objectives, the following specific aims are proposed: 1) Determine whether MCP-1 is required for alcohol-induced liver injury and intracellular mechanisms involved and 2) Investigate the effect of chronic alcohol on CCR2, a MCP-1 receptor, on circulating monocyte/macrophages its functional significance in alcohol-induced liver injury. Public Health Relevance: Alcoholic liver disease is a major health concern in the United States. The objectives of this application are to investigate the effect of CC-chemokine, monocyte chemoattractant protein-1 (MCP-1) and its receptor CC-chemokine receptor 2 (CCR2) on monocyte/macrophages into the liver and its contribution to the development of alcoholic liver injury. These mechanistic studies will identify the role of monocytes and macrophages and aid in developing therapies targeted to inhibit macrophage function during chronic alcohol consumption.

描述（由申请人提供）：从动物模型和人类研究中可以明显看出先天免疫细胞在酒精肝损伤的病理生理学中的重要性。肝脏中的常驻巨噬细胞在门户循环中被内毒素激活以产生炎症性细胞因子。除促炎性细胞因子外，巨噬细胞还产生趋化因子，可导致酒精性肝损伤。我们的初步研究表明，小鼠慢性酒精喂养后血清和肝组织MCP-1产生的产生增加。我们还表明，MCP-1缺乏小鼠在慢性酒精喂养后表现出明显降低的肝损伤。肝脏中的MCP-1增加可以促进肝脏中的单核细胞/巨噬细胞浸润，并导致炎症反应。单核细胞/巨噬细胞的激活对于酒精肝损伤的发展至关重要。 我们假设慢性酒精暴露会在肝脏及其受体中诱导MCP-1循环单核细胞/巨噬细胞的CCR2促进其促进肝脏的募集。因此，MCP-1/CCR2信号的改变可能导致先天免疫细胞介导的酒精肝损伤。当前应用的目标是确定MCP-1/CCR2轴在酒精诱导的肝损伤中的作用。具体而言，我们的重点是首先对肝脏中的MCP-1表达进行纵向分析，并将这些变化与慢性酒精喂养后肝脏中常驻巨噬细胞的变化相关。接下来，我们将在慢性酒精喂养后分析MCP-1受体，CCR2。我们还将在体外测定中确定慢性酒精对表达CCR2单核细胞/巨噬细胞的趋化性的影响。最后，使用CCR2敲除小鼠，我们将确定MCP-1/CCR2轴在酒精诱导的脂肪肝损伤中的病理生理意义。为了实现这些目标，提出了以下特定目标：1）确定酒精诱导的肝损伤和涉及的细胞内机制是否需要MCP-1，2）研究慢性酒精对CCR2的影响，MCP-1受体对MCP-1受体对循环单核细胞/巨噬细胞在酒精诱导的肝损伤中其功能意义。 公共卫生相关性：酒精性肝病是美国的主要健康问题。该应用的目的是研究CC-化学因子，单核细胞趋化蛋白-1（MCP-1）及其受体CC-化学受体2（CCR2）对单核细胞/巨噬细胞及其对肝脏的影响及其对肝脏的影响酒精肝损伤。这些机械研究将确定单核细胞和巨噬细胞的作用，并有助于开发旨在抑制长期饮酒期间巨噬细胞功能的疗法。