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High-mobility group box-1 and alcoholic liver disease

高迁移率族box-1与酒精性肝病

基本信息

批准号：
10451824
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451824
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 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

项目摘要

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.

摘要酒精性肝病（ALD）领域进展的一个关键障碍是缺乏对酒精性肝病（ALD）关键因素的了解。促炎介质及其驱动肝损伤的机制。高迁移率族蛋白B1 （HMGB 1）是一种损伤相关的分子模式，它传递并放大炎症，相邻的细胞。支持这一应用的初步研究表明，HMGB 1增加，经历后，在酒精中毒患者和ALD的小鼠模型中分泌。我们发现肝细胞和库普弗细胞都产生完全还原和乙酰化的HMGB 1，而肝细胞是氧化型HMGB 1的主要来源。我们发现，在肝细胞或骨髓细胞中条件性切除Hmgb 1，部分保护，而两者的缺失防止炎症、白细胞介素-1 β（IL 1 β）产生和ALD。同样，敲低骨髓细胞中晚期糖基化终产物（AGEs）的HMGB 1受体，保护ALD。我们已经发现，在酒精中毒患者中，氧化的HMGB 1与IL 1 β形成复合物，对小鼠总体而言，HMGB 1驱动免疫细胞浸润，激活NFκB并增加促炎性细胞因子的表达。细胞因子IL 1 β，所有ALD发作和进展的中心事件。虽然HMGB 1亚型似乎具有不同的作用;然而，它们中的每一个对酒精诱导的炎症和IL 1 β的精确贡献生产尚未确定。我们认为乙酰化和氧化的HMGB 1水平调节了炎症细胞浸润。这些异构体也可能驱动关键的表达 NFκB靶向促炎细胞因子IL 1 β。由于氧化的HMGB 1与IL 1 β形成复合物，免疫刺激和增强的IL 1 R和/或IL 1 R信号传导。这可能特别重要，因为分子是ALD发病机制的核心。然而，还需要进一步了解异构体导致免疫细胞浸润，涉及的关键受体，它们的结合亲和力，以及它们本身或通过与IL 1 β形成免疫刺激复合物，驱动NFκB诱导IL 1 β mRNA并最终使IL 1 β成熟蛋白质ALD我们的中心假设是乙酰化和氧化的HMGB 1水平调节了 ALD中炎性细胞浸润和IL 1 β产生。计划有两个具体目标来证明这一假设。在目标1中，我们将剖析酒精介导的HMGB 1亚型的增加如何调节炎症细胞，渗入肝脏在目标2中，我们将确定HMGB 1亚型的受体结合亲和力，它们本身发出信号或与IL 1 β形成免疫刺激复合物，以驱动NFκB诱导IL 1 β mRNA， ALD中IL 1 β蛋白的成熟。我们的长期目标是剖析HMGB 1亚型的致病作用作为预防ALD的潜在治疗靶点。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function.

DOI：
10.1016/j.jcmgh.2022.06.012
发表时间：
2022
期刊：
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
影响因子：
7.2
作者：
Das, Sukanta;Song, Zhuolun;Han, Hui;Ge, Xiaodong;Desert, Romain;Athavale, Dipti;Komakula, Sai Santosh Babu;Magdaleno, Fernando;Chen, Wei;Lantvit, Daniel;Guzman, Grace;Nieto, Natalia
通讯作者：
Nieto, Natalia

Danger signals in liver injury and restoration of homeostasis.

DOI：
10.1016/j.jhep.2020.04.033
发表时间：
2020-10
期刊：
Journal of hepatology
影响因子：
25.7
作者：
Han H;Desert R;Das S;Song Z;Athavale D;Ge X;Nieto N
通讯作者：
Nieto N

The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease.

DOI：
10.1002/hep4.1793
发表时间：
2022-01
期刊：
Hepatology communications
影响因子：
5.1
作者：
Das S;Ge X;Han H;Desert R;Song Z;Athavale D;Chen W;Gaskell H;Lantvit D;Guzman G;Nieto N
通讯作者：
Nieto N

High-Mobility Group Box-1 and Liver Disease.

高动力组框1和肝病。