High-mobility group box-1 and alcoholic liver disease

高迁移率族box-1与酒精性肝病

• 批准号: 10197739
• 负责人: Natalia Nieto
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197739
• 关键词: Abbreviations; Ablation; Adhesions; Affinity; Alcoholic Liver Diseases; Alcohols; Architecture; Automobile Driving; Binding; Biological Assay; Cell Adhesion Molecules; Cells; Chemotactic Factors; Chemotaxis; Clinical Trials; Coculture Techniques; Complex; Disease Progression; Ethanol; Event; Generations; Genes; Goals; HMGB1 Protein; Hepatic; Hepatocyte; IL1R1 gene; Immune; Immune response; Immune system; In Vitro; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Knowledge; Kupffer Cells; Lead; Ligands; Liver; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Mus; Myeloid Cells; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Oxides; Pathogenesis; Pathogenicity; Patients; Pattern; Pattern Recognition; Post-Translational Protein Processing; Production; Protein Isoforms; Proteins; Proteomics; Receptor Activation; Research; Role; Signal Transduction; Source; Sterility; Surface Plasmon Resonance; Testing; Tumor-infiltrating immune cells; Validation; Work; alcohol exposure; cytokine; design; effective therapy; experimental study; feeding; in vivo; inhibitor/antagonist; intrahepatic; knock-down; liver injury; macrophage; monocyte; mouse model; neutrophil; novel; novel therapeutics; nucleocytoplasmic transport; overexpression; pathogen; prevent; problem drinker; receptor; receptor binding; receptor for advanced glycation endproducts; response; therapeutic target; tissue injury

ABSTRACT A critical barrier to progress in the field of alcoholic liver disease (ALD) is the lack of knowledge on the key proinflammatory mediators and the mechanisms whereby they drive liver injury. High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that communicates and amplifies inflammation to neighboring cells. Preliminary studies supporting this application reveal that HMGB1 increases, undergoes post- translational modifications and is secreted in alcoholic patients and mouse models of ALD. We identified that both hepatocytes and Kupffer cells produce fully reduced and acetylated HMGB1 whereas hepatocytes are the main source of oxidized HMGB1. We show that conditional ablation of Hmgb1 in hepatocytes or myeloid cells partially protects while deletion in both prevents inflammation, interleukin-1β (IL1β) production and ALD. Likewise, knockdown of the HMGB1 receptor for advanced glycation end-products (RAGE) in myeloid cells protects from ALD. We have identified that oxidized HMGB1 forms a complex with IL1β in alcoholic patients and in mice. Overall, HMGB1 drives immune cell infiltration, activates NFκB and increases the proinflammatory cytokine IL1β, all central events for the onset and progression of ALD. While the HMGB1 isoforms appear to have distinct effects; yet, the precise contribution of each one of them to alcohol-induced inflammation and IL1β production remains undefined. We believe that the levels of acetylated and oxidized HMGB1 regulate inflammatory cell infiltration upon alcohol exposure. These isoforms may also drive the expression of the key NFκB target proinflammatory cytokine IL1β. Since oxidized HMGB1 forms a complex with IL1β, it could be immunostimulatory and enhance RAGE and/or IL1R signaling. This may be particularly relevant as both molecules are central to the pathogenesis of ALD. Yet, further understanding is needed on how the isoforms lead to immune cell infiltration, the key receptor involved, their binding affinity and if they signal per se or via immunostimulatory complexes with IL1β to drive NFκB induction of Il1β mRNA and ultimately maturation of IL1β protein in ALD. Our central hypothesis is that the levels of acetylated and oxidized HMGB1 regulate inflammatory cell infiltration and IL1β production in ALD. Two specific aims are planned to prove this hypothesis. In Aim 1, we will dissect how the alcohol-mediated increase in the HMGB1 isoforms regulates inflammatory cell infiltration into the liver. In Aim 2, we will determine the receptor binding affinity of the HMGB1 isoforms and if they signal per se or form immunostimulatory complexes with IL1β to drive NFκB induction of Il1β mRNA and maturation of IL1β protein in ALD. Our long-term goal is to dissect the pathogenic role of the HMGB1 isoforms as potential therapeutic targets to prevent ALD.

抽象的 酒精性肝病（ALD）领域进步的关键障碍是对密钥缺乏知识 促进介质和驱动肝脏损伤的机制 （HMGB1）是一种与损伤相关的分子赞助人，也可以传达和放大发炎 相邻的细胞。 转化的修饰，并在酒精患者和ALD的小鼠模型中分泌 肝细胞和库普弗细胞都会产生完全减少和脱离的HMGB1 Boreas肝细胞 氧化HMGB1的主要来源。 部分保护，而两者的划痕则可以防止炎症，白介素1β（IL1β）和ALD。 同样，在髓样细胞中敲低HMGB1受体用于晚期糖基化末端（RAGE）的受体 保护ALD。 在整个小鼠中，HMGB1驱动免疫细胞浸润，激活NFκB 细胞因子IL1β，所有中心事件，用于ALD的发作和进展。 有明显的影响； 生产仍然不确定。 酒精暴露时炎性细胞浸润。 NFκB靶向细胞因子IL1β。 免疫刺激器并增强愤怒和/或IL1R信号。 分子是ALD的发病机理的中心。 导致免疫细胞浸润，涉及的关键受体，其结合亲和力以及它们本身发出信号或通过 用IL1β进行免疫刺激复合物，以驱动IL1βmRNA的NFκB指示和IL1β的最终成熟 我们的中心假设中的蛋白质是乙酰化和氧化的HMGB1 ALD中的炎症细胞浸润和IL1β的产生证明是两个特定的。 在AIM 1中，我们将剖析酒精介导的HMGB1同工型调节细胞的增加 在AIM 2中渗入肝脏，我们将确定HMGB1同工型的受体结合 它们本身信号或与Ith ITHIL1β形成免疫刺激复合物，以驱动IL1βmRNA和 ALD中IL1β蛋白的成熟是我们的长期目标。 作为预防ALD的潜在治疗靶标。