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: 8598019
• 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/8598019
• 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; 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; liver injury; 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）： 摘要 长期饮酒与酒精性肝病 (ALD) 的发生有关，酒精性肝病是美国（包括退伍军人）发病和死亡的主要原因。 ALD 的突出特征包括乙醇介导的细胞改变、脂肪变性和肝脏炎症；然而，对所涉及机制的全面了解仍然不完整。先前的研究表明，肝细胞蛋白质运输途径非常容易受到酒精的有害影响。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，我们发现乙醇治疗导致肝细胞特异性脱唾液酸糖蛋白（ASGP）受体的功能明显受损。然而，将观察到的 ASGP 受体功能变化转化为 ALD 的发生率和/或严重程度仍然未知。最近有人提出，免疫细胞的识别和随后的调节可能是 ASGP 受体的潜在生理作用。在该提案的初步研究中，我们已经证明 ASGP 受体与淋巴细胞特异性结合，并且肝受体的缺失会导致肝内 T 细胞的积累并加剧肝损伤。因此，我们认为 ASGP 受体在健康肝脏中免疫细胞的调节中发挥作用，乙醇诱导的 ASGP 受体功能损伤可能导致 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 受体在肝细胞和活化的 T 淋巴细胞（已知在肝损伤后积累的免疫细胞）之间建立联系，从而促进有益地清除潜在损伤的 T 细胞。此外，由于乙醇介导的 ASGP 受体改变，T 细胞清除率发生改变，导致异常淋巴细胞积聚，这些事件可能导致肝炎的发生和 ALD 的进展。我们将通过以下具体目标来解决这些假设： 在初步研究中，将在体外表征 T 淋巴细胞对肝细胞 ASGP 受体的识别和结合。接下来，将分析由于 ASGP 受体介导的肝细胞-淋巴细胞相互作用而触发的淋巴细胞清除机制（吞噬作用和/或 T 细胞死亡机制）。最后，提出体内研究，使用乙醇给药模型以及用诱导剂 T 细胞介导的肝炎治疗的 ASGP 受体敲除小鼠，证明功能性 ASGP 受体改变或缺失在免疫细胞相关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维持肝脏中适当的 T 细胞稳态以及这种相互作用的损害如何导致肝脏疾病加剧的理解。总体而言，这项工作旨在确定并表征肝脏 ASGP 受体在免疫调节中的作用，以及该过程的改变是否会影响肝脏 ASGP 受体的免疫调节。