Regulation of the innate immune response in alcoholic liver disease by autophagy

通过自噬调节酒精性肝病的先天免疫反应

• 批准号: 8785146
• 负责人: Mark J Czaja
• 金额: $ 45.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785146
• 关键词: 5' -AMP-activated protein kinase; Aging; Alcoholic Liver Diseases; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Autophagocytosis; Cells; Cellular Stress; Chronic; Data; Defect; Degradation Pathway; Dependovirus; Development; Diet; Disease; Down-Regulation; Ethanol; Fibrosis; Functional disorder; Generations; Genes; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Immune response; In Vitro; Inflammation; Inflammatory; Injury; Investigation; Knock-out; Knockout Mice; Kupffer Cells; Laboratories; Lead; Lipids; Lipopolysaccharides; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Macrophage Activation; Mediating; Mediator of activation protein; Mitochondria; Molecular; Morbidity - disease rate; Mus; Necrosis; Obesity; Oxidative Stress; Pathway interactions; Phenotype; Prevention; Process; Recruitment Activity; Regulation; Resolution; Role; Signal Pathway; Signal Transduction; Steatohepatitis; Stimulus; Stress; Testing; Therapeutic; Toxin; United States; alcohol effect; alcohol exposure; alcohol response; base; cell growth regulation; chronic liver disease; cofactor; design; fatty acid oxidation; feeding; gain of function; in vivo; inhibition of autophagy; insight; lipid metabolism; liver injury; macrophage; mortality; novel; novel therapeutic intervention; overexpression; oxidation; prevent; problem drinker; public health relevance; response; therapy development

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is one of the most common liver diseases in the United States and a major cause of chronic liver failure and mortality. The mechanisms of liver injury in ALD remain unclear and as a result there is no proven therapy for this disease. Critical to the development of ALD is an overactive hepatic innate immune response. Activated resident Kupffer cells and recruited macrophages generate soluble factors that lead to steatosis, hepatocellular injury and fibrosis. Recent findings indicat that alcohol promotes proinflammatory M1 rather than anti-inflammatory M2 macrophage polarization. Our prior investigations have identified novel functions for the lysosomal, degradative pathway of autophagy in the regulation of cellular signaling pathways and lipid metabolism that mediate M1 and M2 macrophage polarization. The objective of this proposal is to delineate mechanisms by which autophagy regulates macrophage polarization and the hepatic injury that occurs as the result of the overactive proinflammatory response in ALD. Preliminary findings demonstrate that steatosis and alcohol inhibit macrophage autophagy, and that ethanol and impaired autophagy act in concert to block M2 macrophage polarization. In addition, we have generated macrophage- specific mouse knockouts of autophagy and shown that they are sensitized to the development of a proinflammatory response and liver injury from lipopolysaccharide or ethanol. Based on these and other preliminary studies, our central hypothesis is that alcohol impairs macrophage autophagy which promotes proinflammatory macrophage polarization and activation leading to an overactive innate immune response and ALD. We will test this hypothesis in studies contained in three Specific Aims that will delineate the mechanism by which macrophage autophagy is decreased by alcohol, and how this effect alters macrophage polarization and the generation of a hepatic innate immune response to alcohol. First, we will test the hypothesis that alcohol decreases autophagic function in macrophages by inhibiting AMP-activated protein kinase signaling. Second, we will test the hypothesis that an alcohol-induced defect in autophagy promotes M1 and inhibits M2 macrophage polarization through effects on ER stress and mitochondrial ¿-oxidation. Third, we will test the hypothesis that decreased autophagy in macrophages in vivo promotes ALD development by leading to an unrestrained proinflammatory immune response. The objective of these studies is to delineate novel paradigms by which the lysosomal pathway of autophagy regulates the hepatic proinflammatory innate immune response to alcohol. The ultimate goal of these investigations is to better understand the basic cellular mechanisms underlying the development of liver injury from alcohol in order to design new strategies to prevent and treat human ALD.

描述（由申请人提供）：酒精性肝病（ALD）是美国最常见的肝病之一，也是慢性肝功能衰竭和死亡的主要原因。ALD中肝损伤的机制仍不清楚，因此对于这种疾病没有经过证实的治疗方法。ALD发展的关键是过度活跃的肝脏先天免疫反应。激活的常驻枯否细胞和募集的巨噬细胞产生导致脂肪变性、肝细胞损伤和纤维化的可溶性因子。最近的研究结果表明，酒精促进促炎性M1而不是抗炎性M2巨噬细胞极化。我们先前的研究已经确定了溶酶体的新功能，自噬的降解途径在调节细胞信号传导途径和脂质代谢，介导M1和M2巨噬细胞极化。本提案的目的是描述自噬调节巨噬细胞极化和肝损伤的机制，该机制是ALD中过度活跃的促炎反应的结果。初步研究结果表明，脂肪变性和酒精抑制巨噬细胞自噬，乙醇和受损的自噬共同作用，以阻止M2巨噬细胞极化。此外，我们已经产生了巨噬细胞特异性的自噬敲除小鼠，并表明它们对脂多糖或乙醇引起的促炎反应和肝损伤的发展敏感。基于这些和其他初步研究，我们的中心假设是酒精损害巨噬细胞自噬，这促进促炎性巨噬细胞极化和激活，导致过度活跃的先天免疫反应和ALD。我们将在三个特定目标中包含的研究中验证这一假设，这些研究将描述酒精降低巨噬细胞自噬的机制，以及这种效应如何改变巨噬细胞极化和对酒精的肝脏先天免疫反应的产生。首先，我们将检验酒精通过抑制AMP激活的蛋白激酶信号转导降低巨噬细胞自噬功能的假设。第二，我们将检验酒精诱导的自噬缺陷通过对内质网应激和线粒体氧化的影响促进M1和抑制M2巨噬细胞极化的假设。第三，我们将测试的假设，减少在体内巨噬细胞的自噬促进ALD的发展，导致一个不受限制的促炎免疫反应。这些研究的目的是描绘新的范例，其中溶酶体途径的自噬调节肝脏促炎性先天免疫反应酒精。这些研究的最终目标是更好地了解酒精肝损伤发展的基本细胞机制，以设计预防和治疗人类ALD的新策略。