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: 10358521
• 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/10358521
• 关键词: Acute Alcoholic Hepatitis; Affect; Affinity; Alcoholic Liver Diseases; Antibodies; Binding; Biological Assay; Biological Markers; CCL2 gene; CX3CL1 gene; Clinical; Clinical Trials; Complex; Complex Analysis; Data; Disease; Epithelial Cells; Ethanol; Feedback; Functional disorder; Goals; HMGB1 Protein; Hepatic; Hepatocyte; In Vitro; Inflammation; Injury; Interleukin-1 beta; Intestinal permeability; Kupffer Cells; Ligands; Liver; Measures; Molecular; Mus; Myeloid Cells; Oxides; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Phosphoproteins; Production; Risk; 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; macrophage; novel; novel therapeutics; oxidation; prevent; problem drinker; programs; protein complex; protein expression; receptor; receptor binding; receptor for advanced glycation endproducts; response; Acute Alcoholic Hepatitis; Affect; Affinity; Alcoholic Liver Diseases; Antibodies; Binding; Biological Assay; Biological Markers; CCL2 gene; CX3CL1 gene; Clinical; Clinical Trials; Complex; Complex Analysis; Data; Disease; Epithelial Cells; Ethanol; Feedback; Functional disorder; Goals; HMGB1 Protein; Hepatic; Hepatocyte; In Vitro; Inflammation; Injury; Interleukin-1 beta; Intestinal permeability; Kupffer Cells; Ligands; Liver; Measures; Molecular; Mus; Myeloid Cells; Oxides; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Phosphoproteins; Production; Risk; 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; macrophage; novel; novel therapeutics; oxidation; prevent; problem drinker; programs; 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.

抽象的 炎症是酒精引起的肝损伤的标志。大量研究确定了肠道的作用 肝轴，但有关肝脏到肠轴如何促进感染和受伤的信息有限 酒精性肝病。尚不清楚乙醇诱​​导的无菌损伤相关的分子模式是否 肝脏起源激活促炎计划，除了确定肝脏外，还可以驱动肠道 屏障功能障碍，因此在酒精性肝病中产生了放大的促炎反馈回路。我们的 总体目标是剖析肝脏起源蛋白质复合物在调节A中的致病作用 促进酒精性肝病中肝损伤和肠道损伤的促炎计划。 在先前的工作中，我们证明了高动力组Box-1（HMGB1）是损伤相关的分子 响应肝损伤的模式上调，并参与酒精性肝病的发病机理。 有趣的是，HMGB1仅在肝细胞中进行氧化和氧化HMGB1的血清水平 酒精患者（[O] HMGB1）增加。我们的初步数据表明，阻止生产 肝细胞中的[O] HMGB1或减轻HMGB1受体（晚期糖基化末端的受体 产物，愤怒）在髓样细胞中防止感染，肝炎损伤，肠道屏障功能障碍和 酒精性肝病。我们表明，库普弗细胞和浸润的巨噬细胞是主要的肝脏来源 IL1β。重要的是，我们揭示了[O] HMGB1与IL1β形成复合物。这种复合物结合了库普弗的愤怒 细胞和巨噬细胞产生促炎的程序并增加酒精性肝脏的肠道渗透性 疾病。 这些令人鼓舞的数据表明，该复合物引发的促炎反馈循环可以 酒精性肝病中的肝病和肠损伤加剧。但是，如何 这种复合物促进酒精性肝病的发病机理仍有待阐明：1）是否 复合物是肝脏起源； 2）这是否是愤怒的配体； 3）该复合物在库普弗（Kupffer）中传达的信号 细胞和巨噬细胞诱导促炎的程序，加剧肝损伤； 4）是否 改变肠上皮细胞中的紧密连接蛋白表达，并增加肠道屏障功能障碍。 5）促炎计划本身是否也导致肠道屏障功能障碍。 我们提出了肝脏到肠道促炎的反馈回路的概念性新颖框架 疾病。我们的中心假设是，这种复合物是肝脏起源的，并结合了库普弗细胞和 巨噬细胞诱导促炎的计划，加剧肝损伤。通过约束愤怒 肠上皮细胞和/或通过诱导促炎程序，这种复合物改变了紧密的连接 蛋白质表达并增加肠道屏障功能障碍。我们将通过追求三个来检验这一假设 具体目标。在AIM 1中，我们将确定该综合体是肝脏起源的。在AIM 2中，我们将确定 复杂的结合亲和力对库普弗细胞和巨噬细胞中的愤怒，并确定信号 复合体诱导了加剧肝损伤的促炎计划。在AIM 3中，我们将确定是否 复杂的改变紧密的连接蛋白表达，并通过结合愤怒来增加肠道屏障功能障碍 肠上皮细胞和/或通过诱导的促炎程序。因此，针对这个复合物 可能具有巨大的治疗潜力。