Goblet cells and intestinal immune response in alcohol-associated liver disease

酒精相关性肝病中的杯状细胞和肠道免疫反应

• 批准号: 10681329
• 负责人: Ana Cristina Llorente Izquierdo
• 金额: $ 45.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681329
• 关键词: Accounting; Acetylcholine; Adaptive Immune System; Address; Agonist; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Antigen Presentation; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Infections; Bacterial Translocation; Cell Count; Cells; Cellular biology; Cessation of life; Chronic; Cirrhosis; Colon; Complex; Data; Dendritic Cells; Diet; Down-Regulation; Energy-Generating Resources; Epithelial Cells; Equilibrium; Ethanol; Exposure to; Fibrosis; Flow Cytometry; Functional disorder; Generations; Genes; Goals; Goblet Cells; Growth; Healthcare; Human; IL6ST gene; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Innate Immune System; Interleukin-6; Intervention; Intestinal permeability; Intestines; Lamina Propria; Liver; Liver diseases; Mediating; Messenger RNA; Modeling; Monitor; Mucin-2 Staining Method; Mucins; Mucosal Immune System; Mucous body substance; Mus; Muscarinic Acetylcholine Receptor; Myelogenous; Nature; Pathogenesis; Patients; Play; Pre-Clinical Model; Predisposition; Prevention; Preventive therapy; Production; Property; Regulation; Research; Resistance; Risk Factors; Role; Shapes; Signal Pathway; Signal Transduction; Small Intestinal Goblet Cell; Steatohepatitis; Systemic infection; Technology; Therapeutic; Therapeutic Intervention; Time; Transducers; United States; Virus Diseases; Western Blotting; Wild Type Mouse; Woman; adaptive immune response; alcohol exposure; alcohol prevention; alcohol use disorder; care burden; chronic alcohol ingestion; chronic liver disease; chronic liver inflammation; cost; design; dysbiosis; feeding; gain of function; gut dysbiosis; gut microbiota; gut-liver axis; immunoregulation; imprint; in vivo; inhibitor; innovation; intestinal epithelium; intestinal homeostasis; loss of function; men; microbial; microbiome research; microorganism antigen; pathogen; pharmacologic; population health; positive allosteric modulator; prevent; response; systemic inflammatory response

Project Summary/Abstract Excessive alcohol drinking modulates the innate and adaptive immune systems. It is associated with gut dysbiosis and bacterial overgrowth. Consequently, it induces intestinal permeability and microbial translocation to the liver which triggers inflammation aggravating alcohol-associated liver disease. The immune system interacts, tolerates, and shapes the intestinal microbiota while monitoring for pathogens. The balance between gut tolerance and immunity is critical in the regulation of intestinal homeostasis. A balanced intestinal homeostasis is essential to prevent intestinal permeability and microbial translocation to the liver. Goblet cells regulate the intestinal immune response by secreting mucin and presenting luminal antigens to lamina propria dendritic cells (LP-DCs) through goblet-cell associated antigen passages (GAPs). LP-DCs adjacent to GAPs have preferential tolerogenic properties. Chronic alcohol overuse decreases the pool of myeloid DCs and modifies its properties. However, the effect of chronic ethanol overuse on the LP-immune response is not well characterized. The hypothesis is that chronic ethanol exposure alters goblet cell biology resulting in the dysfunction of LP-DCs with tolerogenic properties adjacent to GAPs. Hence, a lack of antigen presentation to tolerogenic LP-DCs would induce an imbalance of the intestinal homeostasis. Therefore, goblet cells might have a central role in the onset of alcohol-related liver diseases. To explore the proposed hypothesis, aim 1 will investigate the impact of chronic alcohol abuse on goblet cell biology. It will assess goblet cell numbers, GAP formation, mucin secretion, and the consequent alterations in the LP-immune system in mice and humans. Aim 2 will define the impact of GAPs and mucin from goblet cells on ethanol-induced liver disease in ethanol-fed mice with both, loss and gain of function approaches. Finally, aim 3 will explore a pharmacological approach to manipulate goblet cells to prevent ethanol-induced liver disease in mice subjected to chronic ethanol feeding. This pharmacological intervention will induce LP-DCs with tolerogenic properties by stimulating GAP formation to regulate the mucosal immune system. The proposed study will characterize the role of goblet cells in preclinical models of ethanol-induced liver disease and patients with alcohol use disorder using cutting edge microbiomics and state-of-the-art technology. The proposed intervention will find innovative strategies to prevent alcohol-associated liver disease in patients.

项目摘要/摘要 过量的酒精饮酒调节先天和适应性免疫系统。它与肠道有关 营养不良和细菌过度生长。因此，它诱导肠道通透性和微生物易位 肝脏引发炎症加剧酒精相关的肝病。免疫系统 在监测病原体的同时，相互作用，耐受和塑造肠菌。之间的平衡 肠道耐受性和免疫力对于调节肠内稳态至关重要。平衡的肠道 稳态对于防止肠道通透性和微生物转移到肝脏至关重要。杯状细胞 通过分泌粘蛋白并将腔抗原呈现给椎板，调节肠道免疫反应 树突状细胞（LP-DCS）通过杯子细胞相关的抗原通道（GAPS）。 LP-DCS与间隙相邻 具有优先的耐受性特性。慢性酒精过度使用会减少髓样DC的池和 修改其属性。但是，慢性乙醇过度使用对LP免疫反应的影响不好 特征。 假设是慢性乙醇暴露会改变杯状细胞生物学，导致功能障碍 具有耐受性特性的LP-DC与间隙相邻。因此，缺乏抗原表现 耐受性LP-DC会引起肠内稳态的失衡。因此，杯状细胞 可能在与酒精相关的肝病发作中起着核心作用。 为了探讨拟议的假设，AIM 1将研究慢性酒精滥用对杯状细胞的影响 生物学。它将评估杯状细胞数，间隙形成，粘蛋白分泌以及随之而来的改变 小鼠和人类中的LP免疫系统。 AIM 2将定义Goblet细胞的间隙和粘蛋白的影响 在乙醇诱导的乙醇喂养小鼠中，功能方法的损失和增益。最后， AIM 3将探索一种药理方法来操纵杯状细胞以防止乙醇诱导的肝脏 接受慢性乙醇进食的小鼠疾病。该药理干预将引起LP-DCS 通过刺激间隙形成来调节粘膜免疫系统，具有耐受性特性。 拟议的研究将表征杯状细胞在乙醇诱导的肝的临床前模型中的作用 使用尖端微生物学和最先进的疾病和酒精使用障碍患者 技术。拟议的干预措施将找到预防酒精相关肝病的创新策略 在患者中。