Immunopathogenesis of Non-alcoholic Fatty Liver Disease

描述（由申请方提供）：肥胖是非酒精性脂肪性肝病（NAFLD）发展的主要风险因素，NAFLD是一系列疾病，从脂肪变性（NAFL）到脂肪性肝炎（NASH）再到肝硬化。尽管其临床和公共卫生意义重大， NAFLD的免疫发病机制仍然不清楚。此外，没有特定的治疗方法可用。因此，对于NAFLD的新的预防和治疗方法存在明确的需求。 IL-17家族细胞因子在屏障免疫、各种自身免疫性疾病的炎症病理学和各种肝病的发病机制中起重要作用。IL-17信号转导诱导细胞因子和中性粒细胞趋化因子产生的能力是IL-17轴生物学效应的核心。我们新的初步数据表明，IL-17轴是NAFL向NASH进展的关键调节因子。具体而言：（a）致肥胖饮食驱动全身和肝脏IL-17 A表达的增加，沿着肝脏GR-1+细胞募集的增加（假定嗜中性粒细胞）;（B）与野生型（WT）对照相比，在IL-17受体复合物成员IL-17 RA中具有遗传缺失的小鼠表现出减少的脂肪性肝炎和肝细胞损伤，尽管在致肥胖饮食攻击后脂肪变性和体重增加;（d）用分节丝状细菌（SFB）（一种通过肠T细胞强烈上调IL-17产生的致病生物）定殖小鼠，加剧肥胖小鼠中的肝细胞损伤，而万古霉素介导的SFB消耗显著降低此类小鼠中的肝细胞损伤;和（e）与WT对照相比，IL-17 RA-/-小鼠表现出与活性氧类（ROS）诱导相关的酶的肝表达降低。综上所述，我们强有力的初步发现和文献中的数据表明了IL-17 A/IL-17 RA轴的激活是NASH发病机制的核心的组织假设。本提案中的研究将：（1）确定在NASH发病机制中重要的IL-17 RA配体;（2）确定对驱动NASH至关重要的IL-17 RA表达细胞类型;和（3）确定对NASH中IL-17轴介导的发病机制至关重要的细胞和分子机制。 本申请的目的是获得IL-17轴在NASH发病机制中的作用的明确机制理解。该计划的长期目标是确定NALFD的新预防和治疗策略。

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.