Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor

酒精改变肝脏免疫功能：去唾液酸糖蛋白受体的作用

• 批准号: 8244030
• 负责人: BENITA L. MCVICKER
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244030
• 关键词: Address; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Feed; Animals; Asialoglycoprotein Receptor; Atypical lymphocyte; Autoimmune Process; Binding; Biochemical; Cell Death; Cell surface; Cells; Cessation of life; Cirrhosis; Clinical; Clinical Treatment; Concanavalin A; Defect; Development; Disease; Ethanol; Event; Excision; Fatty Liver; Goals; Health; Healthcare; Hepatic; Hepatitis; Hepatocyte; Homeostasis; Immune; Impairment; In Vitro; Incidence; Inflammation; Injury; Intervention; Knockout Mice; Knowledge; Laboratories; Lead; Liver; Liver Carbohydrate-Binding Protein; Liver diseases; Lymphocyte; Measures; Mediating; Modeling; Monoclonal Antibody HuM291; Morbidity - disease rate; Outcome; Pathogenicity; Pathway interactions; Phagocytosis; Physiological; Polysaccharides; Population; Predisposition; Process; Regulation; Research; Role; Severities; Signal Transduction; Staging; Substance abuse problem; Surface; Symptoms; T-Lymphocyte; Techniques; Therapeutic Intervention; Transgenic Organisms; Translating; Veterans; Work; alcohol effect; cellular targeting; chronic alcohol ingestion; expectation; immune function; in vivo; innovation; intrahepatic; mortality; problem drinker; programs; protein transport; receptor; receptor function; receptor mediated endocytosis

DESCRIPTION (provided by applicant): ABSTRACT Chronic alcohol consumption is associated with the development of alcoholic liver disease (ALD), a major cause of morbidity and mortality in the U.S. including our Veteran population. Prominent features of ALD include ethanol-mediated cellular alterations, steatosis and hepatic inflammation; however, a comprehensive understanding of the mechanisms involved remains incomplete. It has previously been shown that hepatocellular protein trafficking pathways were found to be highly susceptible to the detrimental effects of alcohol. In particular, our laboratory identified multiple ethanol-induced alterations in the process of receptor- mediated endocytosis (RME) and more specifically, we discovered that ethanol treatment resulted in marked impairments in the function of the hepatocyte-specific asialoglycoprotein (ASGP) receptor. However, translating the observed alterations in ASGP receptor function to the incidence and/or severity of ALD remains uncharacterized. Recently it has been suggested that the recognition and subsequent regulation of immune cells could be a potential physiological role of the ASGP receptor. In preliminary studies for this proposal, we have demonstrated that the ASGP receptor specifically binds to lymphocytes and that the absence of the hepatic receptor results in the accumulation of intrahepatic T cells and enhanced liver injury. Therefore, we propose that the ASGP receptor has a role in the regulation of immune cells in the healthy liver and that ethanol-induced impairments in ASGP receptor function can result in increased liver injury caused by T cell- mediated events. The overall working hypothesis of this study is that ASGP receptors establish connections between hepatocytes and activated T lymphocytes (immune cells that are known to accumulate following liver injury) which facilitate the beneficial removal of potentially damaging T cells. Furthermore, as a consequence of ethanol-mediated alterations to the ASGP receptor, altered clearance of T cells occurs leading to abnormal lymphocyte accumulation, events that could contribute the development of hepatitis and the progression of ALD. We will address these hypotheses with the following specific aims: In initial studies, the recognition and binding of T lymphocytes to the hepatocyte ASGP receptor will be characterized in vitro. Next, lymphocyte clearance mechanisms (phagocytosis and/or T cell death mechanisms) triggered as a result of ASGP receptor- mediated hepatocyte-lymphocyte interactions will be analyzed. And finally, in vivo studies are proposed to demonstrate the importance of altered or absent functional ASGP receptors in the development of immune cell related liver injury using models of ethanol administration along with an ASGP receptor knockout mouse treated with inducers T cell-mediated hepatitis. Information gained from this research can significantly impact our understanding of how hepatocyte-lymphocyte interactions maintain proper T cell homeostasis in the liver and how impairments in such interactions can lead to enhancements in liver disease. Overall, this work aims to establish and characterize the role of the hepatic ASGP receptor in immune regulation and whether the alterations of this proce

描述（由申请人提供）： 抽象的慢性酒精消耗与酒精性肝病（ALD）的发展有关，这是美国包括我们的资深人口的主要原因和死亡率的主要原因。 ALD的突出特征包括乙醇介导的细胞改变，脂肪变性和肝炎；但是，对所涉及机制的全面理解仍然不完整。以前已经显示，发现肝细胞蛋白运输途径非常容易受到酒精的有害作用。特别是，我们的实验室在受体介导的内吞作用（RME）过程中发现了多种乙醇诱导的改变，更具体地说，我们发现乙醇处理导致肝细胞特异性亚溶质蛋白（ASGP）受体的功能显着损害。但是，将观察到的ASGP受体功能的改变变为ALD的发病率和/或严重程度仍然没有表征。最近，有人提出，免疫细胞的识别和后续调节可能是ASGP受体的潜在生理作用。在该提案的初步研究中，我们证明了ASGP受体特异性与淋巴细胞结合，并且缺乏肝受体会导致肝内T细胞的积累和增强的肝损伤。因此，我们建议ASGP受体在健康肝脏中免疫细胞的调节中起作用，并且乙醇诱导的ASGP受体功能损伤会导致T细胞介导的事件引起的肝损伤增加。这项研究的总体工作假设是，ASGP受体在肝细胞与活化的T淋巴细胞（已知会在肝损伤后积累的免疫细胞）之间建立联系，从而有助于消除潜在的破坏性T细胞。此外，由于乙醇介导的对ASGP受体的改变，T细胞的清除率改变导致异常淋巴细胞的积累，可能导致肝炎发展和ALD进展的事件。我们将以以下特定目的解决这些假设：在初步研究中，T淋巴细胞与肝细胞ASGP受体的识别和结合将在体外表征。接下来，将分析淋巴细胞清除机制（吞噬作用和/或T细胞死亡机制），这是由于ASGP受体介导的肝细胞 - 淋巴细胞相互作用而触发的。最后，提出了体内研究，以证明使用乙醇的模型以及用诱导剂T细胞介导的肝炎处理的ASGP受体敲除小鼠，使用乙醇模型以及使用乙醇模型以及使用ASGP受体敲除小鼠的模型来证明改变或没有功能性ASGP受体在与免疫细胞相关的肝损伤发展中的重要性。从这项研究中获得的信息可以显着影响我们对肝细胞 - 淋巴细胞相互作用如何保持肝脏中适当的T细胞稳态以及这种相互作用的损害如何导致肝病的增强。总体而言，这项工作旨在建立和表征肝ASGP受体在免疫调节中的作用，以及该程序的改变是否