Role of Nlrp3 inflammasome signaling in alcoholic liver disease progression

Nlrp3炎症小体信号在酒精性肝病进展中的作用

• 批准号: 505980472
• 负责人: Professor Dr. Alexander Wree
• 金额: --
• 依托单位: Medizinische Klinik mit SP Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505980472?language=en
• 关键词: Role; Nlrp3; inflammasome; signaling; alcoholic

Alcoholic liver disease (ALD) is one of the major disease burdens in western society of our time. Although its prevalence has increased over recent years, disease progression towards severe liver inflammation, liver fibrosis and hepatocellular carcinoma are still not understood. The multi-protein complex NLR family pyrin domain containing 3 inflammasome has been implicated in the promotion of disease progression, boosting cellular inflammation and contributing to differentiation of hepatic stellate cells thereby accelerating the development of fibrosis. These studies fostered the development of novel Nlrp3 inflammasome-interfering compounds, which just entered in the first human studies for the treatment of non-alcoholic fatty liver disease. In previous published studies we demonstrate, that Nlrp3 inflammasome overactivation aggravates the development of liver inflammation and liver fibrosis in mice. In preliminary experiments, we discovered that IL-18 is a driver of hepatic stellate cell activation and alcohol incubation treatment increased hepatocellular IL-18 production. We also analyzed inflammasome-cascade related SNPs in two independent cohorts of patients with hepatocellular cancer and faced a total incidence of 10%. Logically, we propose the HYPOTHESIS that cell-specific Nlrp3 inflammasome activation is a central mechanism that triggers hepatic inflammation and liver fibrogenesis in alcoholic liver disease. Three work packages link evaluation of patient data with in vivo experiments in murine models and advance cell culture and organoid systems. For the latter we will integrate the knowledge and expertise of Prof. Soumita Das (University of California, San Diego), an expert in organoid systems, in our growing liver research unit at Charité Berlin. We will employ multi-celltype coculture with cells either deficient or extensively proficient in Nlrp3 signaling. Consequently, our in vivo experiments are similarly focused on cell specific activation or global deletion of Nlrp3 or IL-18. Combining alcohol in drinking water alongside a Western style diet fed to mice for 8 weeks, will allow a closer delineation of the individual disease components and their role in inflammatory signaling. More specifically, we will employ multi-colour flow cytometry to analyze the individual inflammatory cell subsets in order to project their role in disease progression and therapeutic interventions. Finally, we have established a collaborative effort with Prof. Andreas Heinz (spokesperson of the recently established Collaborative Research Center Transregio 265 – Losing and Regaining Control over Drug Intake) Charité Berlin to evaluate the full spectrum of (ALD) progression. In this cohort of we will evaluate a multiplicity of markers including cytokines, immune cell distribution and microRNA expression. As whole genome sequencing will be performed we will have the unique opportunity to uncover inflammasome cascade alteration in patients with ALD.

酒精性肝病(ALD)是当代西方社会的主要疾病负担之一。尽管近年来其发病率有所增加，但疾病进展为严重的肝脏炎症、肝纤维化和肝细胞癌仍不清楚。含有3个炎症体的NLR家族多蛋白复合体结构域参与促进疾病进展，促进细胞炎症，促进肝星状细胞的分化，从而加速纤维化的发展。这些研究促进了新型Nlrp3炎症组干扰化合物的开发，该化合物刚刚进入治疗非酒精性脂肪性肝病的第一个人体研究。在以前发表的研究中，我们证明，Nlrp3炎症体过度激活会加剧小鼠肝脏炎症和肝纤维化的发展。在初步实验中，我们发现IL-18是肝星状细胞激活的驱动因素，酒精孵育处理增加了肝细胞IL-18的产生。我们还分析了两个独立的肝细胞癌患者队列中与炎症小体-级联相关的SNPs，总发病率为10%。从逻辑上讲，我们提出的假设是，细胞特异性的Nlrp3炎症小体激活是触发酒精性肝病肝脏炎症和肝纤维化的中心机制。三个工作包将患者数据的评估与小鼠模型的体内实验联系起来，并促进细胞培养和有机系统的发展。对于后者，我们将把苏米塔·达斯教授(加州大学圣地亚哥分校)的知识和专业知识整合到我们在柏林夏里特不断发展的肝脏研究部门，他是有机系统方面的专家。我们将采用多种细胞类型与缺乏或广泛精通Nlrp3信号的细胞进行共培养。因此，我们的体内实验同样专注于细胞特异性激活或Nlrp3或IL-18的全局删除。将饮用水中的酒精与西式饮食相结合，给小鼠喂食8周，将允许更近距离地描述单个疾病的组成部分及其在炎症信号中的作用。更具体地说，我们将使用多色流式细胞术来分析单个炎症细胞亚群，以预测它们在疾病进展和治疗干预中的作用。最后，我们与Andreas Heinz教授(最近成立的协作研究中心TransRegio 265-失去和重新获得对药物摄取的控制)Charité柏林建立了一个合作努力，以评估(ALD)进展的全过程。在这个队列中，我们将评估多种标记物，包括细胞因子、免疫细胞分布和microRNA表达。由于将进行全基因组测序，我们将有独特的机会发现ALD患者的炎性小体级联改变。