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: 10446819
• 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/10446819
• 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; Cell physiology; 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; Healthcare; Human; IL6ST gene; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; 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; Patients; Pharmacology; 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; Wild Type Mouse; Woman; adaptive immune response; alcohol exposure; alcohol prevention; alcohol use disorder; base; 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; men; microbial; microbiome research; microorganism antigen; pathogen; 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.

项目概要/摘要 过量饮酒会调节先天性和适应性免疫系统。和肠道有关系 生态失调和细菌过度生长。因此，它诱导肠道通透性和微生物易位 刺激肝脏，引发炎症，加重酒精相关的肝病。免疫系统 在监测病原体的同时，与肠道微生物群相互作用、耐受并塑造肠道微生物群。之间的平衡 肠道耐受性和免疫对于肠道稳态的调节至关重要。平衡的肠道 体内平衡对于防止肠道通透性和微生物易位至肝脏至关重要。杯状细胞 通过分泌粘蛋白并向固有层呈递管腔抗原来调节肠道免疫反应 树突状细胞（LP-DC）通过杯状细胞相关抗原通道（GAP）。与 GAP 相邻的 LP-DC 具有优先耐受性。慢性酒精过度使用会减少骨髓树突状细胞的数量 修改其属性。然而，长期过量使用乙醇对 LP 免疫反应的影响并不明显 特点。 该假设是，长期接触乙醇会改变杯状细胞的生物学特性，导致杯状细胞功能障碍 LP-DC 具有与 GAP 相邻的耐受性。因此，缺乏抗原呈递 耐受性 LP-DC 会导致肠道稳态失衡。因此，杯状细胞 可能在酒精相关肝病的发生中起核心作用。 为了探索所提出的假设，目标 1 将研究长期酗酒对杯状细胞的影响 生物学。它将评估杯状细胞数量、GAP 形成、粘蛋白分泌以及随后的变化 小鼠和人类的 LP 免疫系统。目标 2 将定义杯状细胞的 GAP 和粘蛋白的影响 通过功能丧失和获得两种方法来治疗乙醇喂养的小鼠中乙醇引起的肝病。最后， 目标 3 将探索一种操纵杯状细胞预防乙醇诱导性肝病的药理学方法 长期喂食乙醇的小鼠患上这种疾病。这种药物干预将诱导 LP-DC 通过刺激 GAP 形成来调节粘膜免疫系统，从而具有耐受性。 拟议的研究将描述杯状细胞在乙醇诱导的肝脏临床前模型中的作用 使用最先进的微生物组学和最先进的技术来研究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性肝病的创新策略 在患者中。