Immunopathogenesis of Non-alcoholic Fatty Liver Disease

描述(申请人提供)：肥胖是发展非酒精性脂肪性肝病(NAFLD)的主要风险因素，NAFLD是一系列疾病，从脂肪变性(NAFL)、脂肪性肝炎(NASH)到肝硬变。尽管它对临床和公共卫生具有重要意义， NAFLD的免疫发病机制尚不清楚。此外，目前还没有特定的治疗方法。因此，显然需要对NAFLD采取新的预防和治疗方法。IL-17家族细胞因子在多种自身免疫性疾病的屏障免疫、炎性病理以及多种肝病的发病机制中发挥重要作用。IL-17信号诱导细胞因子和中性粒细胞趋化因子的产生是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发展的关键调节因子。具体地说：(A)肥胖饮食导致全身和肝脏IL-17A表达增加，同时肝脏GR-1+细胞(假定为中性粒细胞)招募增加；(B)与野生型(WT)对照组相比，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，尽管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中和显著减少了肥胖相关的肝细胞损害；(D)节段性丝状细菌(SFB)是一种能强烈上调肠道T细胞产生IL-17的病原体，可加剧肥胖小鼠的肝细胞损伤--而万古霉素介导的SFB缺失可显著减少此类小鼠的肝细胞损伤；(E)与WT对照组相比，IL-17RA-/-小鼠肝脏中与诱导活性氧自由基(ROS)相关的酶的表达减少。综上所述，我们强有力的初步发现和文献中的数据表明，IL-17A/IL-17RA轴的激活是NASH发病机制的核心。这项研究将：(1)确定IL-17RA配体(S)在NASH发病中的重要作用；(2)确定IL-17RA表达的细胞类型(S)对驱动NASH至关重要；(3)确定IL-17轴介导的NASH发病的细胞和分子机制。这项应用的目的是从机制上清楚地了解IL-17轴在NASH发病机制中的作用。该计划的长期目标是确定NALFD的新的预防和治疗策略。

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.