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

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标志。许多研究确定了肠道对 肝轴，但关于肝-肠轴如何促进炎症和损伤的信息有限， 酒精性肝病目前尚不清楚乙醇诱导的不育性损伤相关的分子模式是否与细胞凋亡有关。 肝源激活促炎程序，除了对肝脏有害外， 屏障功能障碍，从而在酒精性肝病中产生放大的促炎反馈回路。我们 总体目标是剖析肝源性蛋白复合物在调节肝细胞凋亡中的致病作用， 导致酒精性肝病肝脏和肠道损伤的促炎程序。 在先前的工作中，我们证明了高迁移率族蛋白1（HMGB 1）是一种损伤相关分子， 在肝损伤时上调，参与酒精性肝病的发病机制。 有趣的是，HMGB 1仅在肝细胞中发生氧化，血清中氧化的HMGB 1 （[O] HMGB 1）在酒精中毒患者中升高。我们的初步数据表明， 或消融HMGB 1受体（晚期糖基化终末产物的受体）。 产品，在骨髓细胞中预防炎症，肝损伤，肠屏障功能障碍， 酒精性肝病我们发现枯否细胞和浸润的巨噬细胞是主要的肝细胞来源。 IL 1 β。重要的是，我们揭示了[O] HMGB 1与IL 1 β形成复合物。该复合物结合Kupffer中的Escherichia 细胞和巨噬细胞产生促炎程序，并增加酒精性肝的肠道通透性 疾病 这些令人鼓舞的数据表明，由这种复合物启动的促炎反馈回路， 加重酒精性肝病的肝和肠损伤。然而，关键的机械方面， 这种复合物促进酒精性肝病的发病机制仍有待阐明：1）是否这 复合物是否为肝源性; 2）它是否是一个配体; 3）该复合物在Kupffer中传递的信号 细胞和巨噬细胞诱导促炎程序，加剧肝损伤; 4）是否 改变肠上皮细胞中紧密连接蛋白的表达并增加肠屏障功能障碍; 和5）促炎程序本身是否也有助于肠屏障功能障碍。 我们提出了一个概念上的新框架，即酒精性肝的肝-肠促炎反馈回路 疾病我们的中心假设是，这种复合物是肝脏来源的，并结合枯否细胞中的β-内酰胺酶， 巨噬细胞诱导加重肝损伤的促炎程序。通过绑定连接 肠上皮细胞和/或通过诱导促炎程序，该复合物改变紧密连接 蛋白质表达并增加肠屏障功能障碍。我们将通过以下三个方面来检验这一假设： 具体目标。在目标1中，我们将确定复合物为肝脏来源。在目标2中，我们将确定 Kupffer细胞和巨噬细胞中对BMP 2的复杂结合亲和力，并确定 复合物诱导了加重肝损伤的促炎程序。在目标3中，我们将确定 复合物通过结合肠粘连蛋白改变紧密连接蛋白表达并增加肠屏障功能障碍 肠上皮细胞和/或通过诱导促炎程序。因此，针对这个复杂的 可能有很大的治疗潜力