Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）是一系列进行性疾病， 肝脏（NAFL）或肝脏脂肪变性至更严重的非酒精性脂肪性肝炎（NASH），其特征在于 过度炎症和不同程度的纤维化。NASH相关的肝硬化是导致肝硬化的第二大原因。 美国的肝移植和NASH患者面临肝细胞癌风险增加， carcinoma. NASH和NASH相关肝硬化的发病率持续上升;没有FDA批准的 治疗，因为我们缺乏对细胞和分子机制的明确理解，推动进展， NAFL到NASH以及随后肝硬化的发展。虽然有越来越多的证据表明炎症 是NAFLD的启动和进展的核心，NAFLD是驱动炎症的特异性免疫途径， 这种设置还没有被很好地理解。本提案的目的是提高我们对以下方面的职能理解： 免疫细胞促进NASH相关肝脏炎症的机制，并确定免疫细胞促进NASH相关肝脏炎症的关键机制。 免疫细胞向肝脏募集的分子。我们发表的研究结果和初步数据 表明异二聚体整合素受体α 4 β 7及其配体，粘膜地址素细胞粘附 分子-1（MAdCAM-1），通过促进NASH相关的肝脏炎症和纤维化， 炎症单核细胞和CD4 T细胞向肝脏的募集。这些数据提供了科学依据 对于我们的中心假设，即α 4 β 7/MAdCAM-1轴通过以下方式驱动NASH中的肝脏炎症和纤维化： 促进促炎单核细胞和CD4 T细胞向肝脏的募集。我们将测试这个假设， 进行性NAFLD的小鼠模型和来自NASH患者的人肝组织中， 综合具体目标。目的1将研究α 4 β 7+单核细胞和CD4 T细胞在肿瘤中的作用。 促进NASH中的肝脏炎症。目的2着重于肝星状细胞在调节 免疫细胞向NASH肝脏的募集。最后，目标3研究了调节 NASH中的α 4 β 7/MAdCAM-1轴。我们的调查结果将提供全面和机械的 对NASH发病机制至关重要的炎症事件的见解，并可能导致识别 用于调节肝脏炎症的可行的治疗靶点。鉴于免疫细胞在控制 代谢性炎症和靶向免疫细胞的治疗潜力，该提案解决了 NASH中的重要和临床相关问题。

PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a spectrum of progressive conditions ranging from nonalcoholic fatty liver (NAFL) or hepatic steatosis to the more severe nonalcoholic steatohepatitis (NASH) characterized by excessive inflammation and varying degrees of fibrosis. NASH-related cirrhosis is the second leading cause of liver transplantation in the United States and NASH patients face an increased risk of developing hepatocellular carcinoma. The incidence of NASH and NASH-related cirrhosis continues to rise; there, are no FDA-approved therapies as we lack a clear understanding of the cellular and molecular mechanisms driving the progression of NAFL to NASH and the subsequent development of cirrhosis. While there is mounting evidence that inflammation is central to the initiation and progression of NAFLD, the specific immune pathways that drive inflammation in this setting are not well understood. The objective of this proposal is to improve our functional understanding of the mechanisms by which immune cells contribute to NASH-related hepatic inflammation, and to identify the key molecules underlying recruitment of immune cells to the liver. Our published findings and preliminary data have demonstrated that the heterodimeric integrin receptor α4β7 and its ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), play a pivotal role in NASH-related hepatic inflammation and fibrosis by promoting the recruitment of inflammatory monocytes and CD4 T cells to the liver. These data provide the scientific rationale for our central hypothesis that the α4β7/MAdCAM-1 axis drives hepatic inflammation and fibrosis in NASH by promoting recruitment of proinflammatory monocytes and CD4 T cells to the liver. We will test this hypothesis in both a mouse model of progressive NAFLD and in human liver tissue from NASH patients according to the following integrated Specific Aims. Aim 1 will investigate the contribution of α4β7+ monocytes and CD4 T cells in promoting hepatic inflammation in NASH. Aim 2 focuses on the role of hepatic stellate cells in the regulation of immune cell recruitment to the NASH liver. Lastly, Aim 3 investigates the mechanisms regulating the α4β7/MAdCAM-1 axis in NASH. The results of our investigations will provide comprehensive and mechanistic insights into the inflammatory events crucial to the pathogenesis of NASH, and may lead to the identification of viable therapeutic targets for regulating hepatic inflammation. Given the importance of immune cells in governing metabolic inflammation and the therapeutic potential of targeting immune cells, this proposal addresses significant and clinically relevant issues in NASH.