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The role of Kupffer cells in alcohol-induced liver disease

库普弗细胞在酒精性肝病中的作用

基本信息

批准号：
9761401
负责人：
YASUKO IWAKIRI
金额：
$ 37.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761401
关键词：
Adoptive Transfer Alcohol abuse Alcoholic Fatty Liver Alcoholic Hepatitis Alcoholic Liver Diseases Animals Anti-inflammatory B-Lymphocytes Cells Cirrhosis Clinical Data Development Diet Early Intervention Encapsulated Endoplasmic Reticulum Endothelial Cells Enhancers Ethanol Exhibits Fatty Liver Fibrosis Goals Hepatic Stellate Cell Hepatocyte Human In Vitro Inflammatory Inflammatory Response Injury Interleukin-1 beta Knock-out Knockout Mice Kupffer Cells Light Link Liver Liver diseases Molecular Mus NOS2A gene Nuclear Patients Play Primary carcinoma of the liver cells Proteins Reporting Research Role Severities Small Interfering RNA Specimen Structure TNF gene Testing Therapeutic alcohol response arginase base chronic alcohol ingestion effective therapy endoplasmic reticulum stress experimental study factor A in vivo liver injury macrophage nanoparticle non-alcoholic novel paracrine polarized cell prevent problem drinker response therapeutic target

项目摘要

SUMMARY Alcohol-induced liver disease is a significant clinical problem. Kupffer cells (liver resident macrophages) play crucial roles in the inflammatory responses of alcoholic liver disease. Macrophages have distinct functional states with pro-inflammatory M1 type and anti-inflammatory M2 type. The mechanisms that govern this classical polarization remain to be elucidated. The goals of this study are to: 1) Identify a novel molecular switch that determines M1 vs. M2 polarization in the context of ethanol- induced hepatic steatosis and injury and 2) Evaluate the potential of Kupffer cells as a therapeutic target. An endoplasmic reticulum (ER) resident protein, Nogo-B, also known as reticulon 4B, has been implicated in maintaining ER structure. In the liver, Nogo-B is restricted to non-parenchymal cells including Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells, but not in hepatocytes. Our preliminary data demonstrate that Nogo-B levels correlate with the severity of alcoholic liver disease in patients. Nogo-B levels in Kupffer cells were positively associated with M1 polarization and negatively with M2 polarization in human liver specimens. In mice, the absence of Nogo-B resulted in significantly lower levels of hepatic steatosis and injury than wildtype (WT) mice in response to an ethanol diet. Kupffer cells from Nogo-B knockout (KO) mice showed significantly decreased expression of M1 markers, including inducible nitric oxide synthase (iNOS), interleukin 1β (IL1β) and tumor necrosis factor α (TNFα), but exhibited significantly increased M2 markers, such as CD163 and arginase-1, compared to their WT counterparts. Importantly, iNOS, IL1β and TNFα have been reported to enhance hepatic steatosis in alcoholic or non-alcoholic settings and are induced by nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB). Nogo-B KO Kupffer cells exhibited significantly increased ER stress, a factor that induces M2 polarization. Based on these observations from human specimens and animal studies, we hypothesize that Nogo-B regulates Kupffer cell polarization and facilitates hepatic steatosis/injury in response to chronic ethanol consumption and that selective deletion of Nogo-B in Kupffer cells will reduce ethanol-induced hepatic injury. To test these hypotheses, we propose the following three aims: 1) Determine the mechanism by which Nogo-B facilitates M1 polarization of Kupffer cells in response to chronic ethanol consumption, 2) Determine the mechanism by which lack of Nogo-B facilitates M2 polarization of Kupffer cells in response to chronic ethanol consumption, and 3) Determine whether deletion of Nogo-B in Kupffer cells reduces hepatic steatosis and injury in ethanol-fed mice.

总结