Pathogenic role of a protein complex of liver origin as regulator of a proinflammatory program that drives hepatic and intestinal injury in alcoholic liver disease

肝脏来源的蛋白质复合物作为促炎程序的调节剂的致病作用，该程序驱动酒精性肝病中的肝脏和肠道损伤

• 批准号: 10663785
• 负责人: Natalia Nieto
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663785
• 关键词: Ablation; Acute Alcoholic Hepatitis; Affect; Affinity; Alcoholic Liver Diseases; Antibodies; Binding; Biological Assay; Biological Markers; CCL2 gene; CX3CL1 gene; Clinical; Clinical Trials; Complex; Data; Disease; Epithelial Cells; Ethanol; Feedback; Functional disorder; Goals; HMGB1 gene; Hepatic; Hepatocyte; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Intestinal permeability; Kupffer Cells; Ligands; Liver; Macrophage; Measures; Molecular; Mus; Myeloid Cells; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Phosphoproteins; Prediction of Response to Therapy; Production; Role; Sampling; Serum; Signal Transduction; Source; Sterility; TNF gene; Testing; Therapeutic; Tight Junctions; Treatment outcome; Veterans; Work; cytokine; design; feeding; in vitro testing; in vivo; intestinal barrier; intestinal epithelium; intestinal injury; liver injury; novel; novel therapeutics; oxidation; prevent; problem drinker; programs; progression risk; protein complex; protein expression; receptor; receptor binding; receptor for advanced glycation endproducts; response

ABSTRACT Inflammation is a hallmark of alcohol-induced liver injury. Numerous studies established the role of the gut-to- liver axis, but there is limited information on how the liver-to-gut axis contributes to inflammation and injury in alcoholic liver disease. It is unknown whether ethanol-induced sterile damage-associated molecular patterns of liver origin activate a proinflammatory program that, besides being detrimental to the liver, drive intestinal barrier dysfunction, hence creating an amplifying proinflammatory feedback loop in alcoholic liver disease. Our overarching goal is to dissect the pathogenic role of a protein complex of liver origin in regulating a proinflammatory program that drives hepatic and intestinal injury in alcoholic liver disease. In prior work, we demonstrated that high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern up-regulated in response to liver injury and participates in the pathogenesis of alcoholic liver disease. Interestingly, HMGB1 undergoes oxidation only in hepatocytes, and serum levels of oxidized HMGB1 ([O]HMGB1) are increased in alcoholic patients. Our preliminary data demonstrate that blocking the production of [O]HMGB1 in hepatocytes or ablating an HMGB1 receptor (the receptor for advanced glycation end- products, RAGE) in myeloid cells prevents inflammation, hepatic injury, intestinal barrier dysfunction and alcoholic liver disease. We show that Kupffer cells and infiltrated macrophages are the main hepatic source of IL1β. Importantly, we reveal that [O]HMGB1 forms a complex with IL1β. This complex binds RAGE in Kupffer cells and macrophages to produce a proinflammatory program and increases gut permeability in alcoholic liver disease. These encouraging data suggest that a proinflammatory feedback loop initiated by this complex, could exacerbate hepatic and intestinal injury in alcoholic liver disease. However, key mechanistic aspects of how this complex promotes the pathogenesis of alcoholic liver disease remain to be elucidated: 1) whether this complex is of liver origin; 2) whether it is a ligand for RAGE; 3) the signals this complex conveys in Kupffer cells and macrophages to induce a proinflammatory program that exacerbates hepatic injury; 4) whether it alters tight junction protein expression in intestinal epithelial cells and increases intestinal barrier dysfunction; and 5) whether the proinflammatory program itself also contributes to intestinal barrier dysfunction. We propose a conceptually novel framework of a liver-to-gut proinflammatory feedback loop in alcoholic liver disease. Our central hypothesis is that this complex is of liver origin and binds RAGE in Kupffer cells and macrophages to induce a proinflammatory program that exacerbates hepatic injury. By binding RAGE in intestinal epithelial cells and/or by inducing the proinflammatory program, this complex alters tight junction protein expression and increases intestinal barrier dysfunction. We will test this hypothesis by pursuing three specific aims. In Aim 1, we will identify the complex as being of liver origin. In Aim 2, we will determine the complex binding affinity for RAGE in Kupffer cells and macrophages and identify the signals through which the complex induces a proinflammatory program that exacerbates hepatic injury. In Aim 3, we will determine if the complex alters tight junction protein expression and increases intestinal barrier dysfunction by binding RAGE in intestinal epithelial cells and/or by inducing the proinflammatory program. Therefore, targeting this complex could have significant therapeutic potential.

摘要 炎症是酒精性肝损伤的一个特征。许多研究都证实了肠胃的作用。 肝轴，但关于肝脏到肠轴如何在炎症和损伤中起作用的信息有限 酒精性肝病。目前尚不清楚乙醇诱导的不育损伤相关的分子模式 肝脏来源激活了一种促炎症程序，除了对肝脏有害外，还推动肠道 屏障功能障碍，因此在酒精性肝病中创建了一个放大的促炎反馈循环。我们的 首要目标是剖析一种源于肝脏的蛋白质复合体在调节 促进酒精性肝病中肝脏和肠道损伤的促炎程序。 在以前的工作中，我们证明了高迁移率基团盒-1(HMGB1)是一种损伤相关分子 Pattera在应对肝损伤时表达上调，并参与酒精性肝病的发病机制。 有趣的是，HMGB1只在肝细胞中经历氧化，而血清中氧化的HMGB1水平 酒精中毒患者([O]HMGB1)升高。我们的初步数据显示，阻止生产 或消融HMGB1受体(晚期糖基化终末受体)。 髓系细胞中的RAGE)可预防炎症、肝损伤、肠屏障功能障碍和 酒精性肝病。我们发现Kupffer细胞和浸润性巨噬细胞是肝脏的主要来源。 IL-1β。重要的是，我们揭示了[O]HMGB1与IL1β形成络合物。这个情结将愤怒捆绑在库普弗 细胞和巨噬细胞产生促炎程序并增加酒精性肝脏的肠道通透性 疾病。 这些令人鼓舞的数据表明，由这个复合体启动的促炎反馈环路可能 加重酒精性肝病的肝脏和肠道损伤。然而，关键的机制方面是如何 该复合体促进酒精性肝病的发病机制尚待阐明：1)这种复合体 复合体起源于肝脏；2)它是否是愤怒的配基；3)该复合体在库普弗传递的信号 细胞和巨噬细胞诱导促炎程序，从而加剧肝脏损伤；4)是否 改变肠上皮细胞紧密连接蛋白的表达，增加肠屏障功能障碍； 5)促炎计划本身是否也导致肠屏障功能障碍。 在酒精性肝脏中，我们提出了一个新的概念框架，即肝脏到肠道的促炎反馈环 疾病。我们的中心假设是这种复合体起源于肝脏，并与库普弗细胞和 巨噬细胞诱导促炎程序，从而加剧肝脏损伤。通过将愤怒绑定在 肠上皮细胞和/或通过诱导促炎程序，这种复合体改变紧密连接 蛋白质的表达，并增加肠道屏障功能障碍。我们将通过追求三个方面来检验这一假设 明确的目标。在目标1中，我们将确定该复合体来自肝脏。在目标2中，我们将确定 Kupffer细胞和巨噬细胞中RAGE的复杂结合亲和力，并确定通过什么信号 复合体诱导促炎程序，加剧肝脏损伤。在目标3中，我们将确定是否 复合体通过结合RAGE改变紧密连接蛋白的表达并增加肠屏障功能障碍 肠道上皮细胞和/或通过诱导促炎程序。因此，针对这个综合体 可能有很大的治疗潜力。