Immunopathogenesis of Non-alcoholic Fatty Liver Disease

非酒精性脂肪肝的免疫发病机制

• 批准号: 8729485
• 负责人: Senad Divanovic
• 金额: $ 33.28万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729485
• 关键词: Antibodies; Autoimmune Diseases; Automobile Driving; Bacteria; Biological; Bone Marrow; Cardiovascular Diseases; Cells; Chronic Disease; Chronic Hepatitis C; Cirrhosis; Clinical; Complex; Data; Development; Diet; Disease; Enzymes; Exhibits; Family; Fatty Liver; Genetic; Glucose Intolerance; Goals; Grant; Hepatic; Hepatocellular Damage; Hepatocyte; Human; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Interleukin-17; Intestines; Ischemia; Kupffer Cells; Ligands; Literature; Liver; Liver diseases; Lymphocyte; Mediating; Metabolic; Molecular; Morbidity - disease rate; Mus; Neutrophil Infiltration; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Preventive; Production; Public Health; Reactive Oxygen Species; Regulation; Reperfusion Therapy; Research; Risk Factors; Role; Signal Transduction; Steatohepatitis; T-Lymphocyte; Techniques; Testing; Therapeutic; Vancomycin; Vascular Diseases; Weight Gain; Western World; Wild Type Mouse; base; cell type; chemokine; chronic liver disease; cytokine; insight; liver injury; liver transplantation; macrophage; member; neutrophil; non-alcoholic fatty liver; novel; programs; public health relevance; receptor; therapeutic target

DESCRIPTION (provided by applicant): Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD), a spectrum of disorders ranging from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. Despite its clinical and public health significance, the mechanisms underlying the immunopathogenesis of NAFLD remain under-defined. Further, no specific therapies are available. Thus, there is a clear need for novel preventive and therapeutic approaches to NAFLD. The IL-17 family of cytokines plays an essential role in barrier immunity, inflammatory pathology in various autoimmune diseases, and in the pathogenesis of diverse hepatic diseases. The ability of IL-17 signaling to induce the production of cytokines and neutrophil chemokines is central to the biological effects of IL-17 axis. Our novel Preliminary Data indicate that the IL-17 axis is a critical regulator of the progression of NAFL to NASH. Specifically: (a) obesogenic-diets drive increases in systemic and hepatic IL-17A expression, along with increased recruitment of hepatic GR-1+ cells (presumed neutrophils); (b) compared to wild-type (WT) controls, mice with a genetic deletion in the IL-17 receptor complex member IL-17RA exhibit decreased steatohepatitis and hepatocellular damage despite increased steatosis and weight gain after obesogenic diet challenge; (c) antibody-mediated neutralization of IL-17A significantly reduces obesity-associated hepatocellular damage; (d) colonization of mice with segmented filamentous bacteria (SFB), a pathobiont that robustly upregulates IL-17 production by intestinal T cells, exacerbates hepatocellular damage in obese mice- whereas vancomycin- mediated depletion of SFB significantly reduces hepatocellular damage in such mice; and (e) compared to WT controls, IL-17RA-/- mice, exhibit decreased hepatic expression of enzymes associated with induction of reactive oxygen species (ROS). Taken together, our strong preliminary findings and the data in the literature suggest the organizing hypothesis that activation of the IL-17A/IL-17RA axis is central to the pathogenesis of NASH. Studies in this proposal will: (1) determine the IL-17RA ligand(s) important in NASH pathogenesis; (2) define the IL-17RA-expressing cell type(s) critical for driving NASH; and (3) define the cellular and molecular mechanisms central to IL-17 axis-mediated pathogenesis in NASH. The goal of this application is to gain a clear mechanistic understanding of the role of IL-17 axis in the pathogenesis of NASH. The long-term goal of this program is to identify novel preventive and therapeutic strategies for NALFD.

描述（由申请人提供）：肥胖是发生非酒精性脂肪性肝病（NAFLD）的主要危险因素，这是一系列从脂肪变性（NAFL）到脂肪性肝炎（NASH）到肝硬化的疾病。尽管其具有临床和公共卫生意义， NAFLD 的免疫发病机制仍不明确。此外，没有可用的具体疗法。因此，显然需要新的 NAFLD 预防和治疗方法。 IL-17 细胞因子家族在屏障免疫、各种自身免疫性疾病的炎症病理学以及各种肝脏疾病的发病机制中发挥着重要作用。 IL-17 信号传导诱导细胞因子和中性粒细胞趋化因子产生的能力对于 IL-17 轴的生物学效应至关重要。我们新颖的初步数据表明，IL-17 轴是 NAFL 进展为 NASH 的关键调节因子。具体来说：(a) 致胖饮食会增加全身和肝脏 IL-17A 表达，同时增加肝脏 GR-1+ 细胞（推测为中性粒细胞）的募集； (b)与野生型（WT）对照相比，IL-17受体复合体成员IL-17RA基因缺失的小鼠表现出脂肪性肝炎和肝细胞损伤减少，尽管在致肥胖饮食挑战后脂肪变性和体重增加增加； (c) 抗体介导的 IL-17A 中和显着减少肥胖相关的肝细胞损伤； (d) 分节丝状细菌（SFB）是一种能够强烈上调肠道 T 细胞产生 IL-17 的病原体，在小鼠中定植会加剧肥胖小鼠的肝细胞损伤，而万古霉素介导的 SFB 耗竭可显着减少此类小鼠的肝细胞损伤； (e)与WT对照相比，IL-17RA-/-小鼠表现出与活性氧(ROS)诱导相关的酶的肝脏表达降低。总而言之，我们强有力的初步研究结果和文献中的数据表明了这样的组织假设：IL-17A/IL-17RA 轴的激活是 NASH 发病机制的核心。本提案中的研究将：（1）确定在 NASH 发病机制中重要的 IL-17RA 配体； (2) 定义对于驱动 NASH 至关重要的表达 IL-17RA 的细胞类型； (3) 定义 NASH 中 IL-17 轴介导的发病机制的核心细胞和分子机制。 本申请的目标是对 IL-17 轴在 NASH 发病机制中的作用获得清晰的机制了解。该计划的长期目标是确定 NALFD 的新预防和治疗策略。