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

项目摘要/摘要 过量饮酒会调节先天免疫系统和适应性免疫系统。它与肠子有关 生物失调和细菌过度生长。因此，它会导致肠道通透性和微生物移位。 对肝脏会引发炎症，加重与酒精相关的肝病。免疫系统 在监测病原体的同时，相互作用、容忍和塑造肠道微生物区系。两者之间的平衡 肠道耐受和免疫在肠道内稳态的调节中起着至关重要的作用。平衡的肠道 动态平衡是防止肠道通透性和微生物移位到肝脏的关键。杯状细胞 通过分泌粘蛋白和向固有层递送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)。Lp-毗邻Gap的DC 具有优先的耐受性。长期酗酒会减少髓系树突状细胞和 修改其属性。然而，长期过量饮酒对LP免疫反应的影响并不理想 特色化的。 假设是慢性酒精暴露改变了杯状细胞的生物学，导致了 与间隙相邻的具有耐受性的LP-DC。因此，缺乏抗原呈递给 耐受性LP-DC会引起肠道内环境平衡失衡。因此，高脚杯细胞 可能在酒精相关肝病的发病中起核心作用。 为了探索提出的假设，目标1将调查慢性酒精滥用对杯状细胞的影响 生物学。它将评估杯状细胞的数量、缝隙的形成、粘蛋白的分泌以及由此引起的 小鼠和人类的LP免疫系统。目标2将定义杯状细胞间隙和粘蛋白的影响 从功能损失性和获得性两个方面探讨酒精所致小鼠肝病。最后， 目标3将探索一种药理学方法来操纵杯状细胞来预防乙醇诱导的肝脏 慢性酒精喂养的小鼠的疾病。这种药物干预将诱导LP-DC 通过刺激缝隙的形成来调节粘膜免疫系统，从而具有耐受性。 这项拟议的研究将描述杯状细胞在酒精性肝病临床前模型中的作用。 使用尖端微生物学和最新技术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肝病的创新策略 在病人身上。

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.