Role of gp91phox in Hepatic MF Programming and Alcohol Liver Disease

gp91phox 在肝脏 MF 编程和酒精性肝病中的作用

• 批准号: 9129373
• 负责人: Cynthia Ju
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129373
• 关键词: Accounting; Acute; Adrenal Cortex Hormones; Affect; Aftercare; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Bone Marrow; Cells; Cessation of life; Chimera organism; Chronic; Cues; Data; Development; Disease; Ethanol; Genes; Goals; Heavy Drinking; Hepatic; Heterogeneity; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Knowledge; Kupffer Cells; Liver; Liver Cirrhosis; Liver diseases; Metabolic; Modeling; Molecular; Mouse Strains; Mus; NADPH Oxidase; Natural Immunity; Pathogenesis; Patients; Pentoxifylline; Phagocytosis; Pharmacologic Substance; Phenotype; Play; Population; Population Heterogeneity; Predisposition; Research; Risk Factors; Role; Staging; Tissues; base; cell type; chronic liver disease; feeding; in vivo; insight; liver inflammation; liver injury; liver transplantation; macrophage; mouse model; novel therapeutics; programs; public health relevance; research study; restoration; therapeutic development; therapeutic target

 DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) affects more than 10 million people in the U.S. and accounts for nearly half of liver cirrhosis-associated deaths. A better understanding of the pathogenesis of the disease is necessary to develop new therapies, which are currently quite limited. The innate immune system plays an important role in the pathogenesis of ALD. Macrophages (MΦ) is a major type of cells of the innate immunity, and has emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Evidence suggests that hepatic MΦ s are important in the development and progression of ALD. In patients and animal models, increased numbers of hepatic MΦ are found in all stages of ALD, and factors indicating MΦ activation are elevated. Hepatic MΦ s are a heterogeneous population with diverse phenotype and functions. Aside from resident Kupffer cells (KCs), we recently discovered that chronic ethanol feeding to mice causes the hepatic recruitment of infiltrating MΦ s (IMs), which consist of a pro-inflammatory Ly6Chi subset and an anti- inflammatory, tissue-protective Ly6Clow subset. Phagocytosis of dead cells (efferocytosis) promotes the switching of Ly6Chi IMs to Ly6Clow IMs. Moreover, we found that hepatic MΦ s from gp91phox-/- mice have impaired efferocytosis ability. Interestingly, compared with ethanol-fed WT mice, the ratio of Ly6Chi/Ly6Clow IMs, as well as the degree of liver injury, are significantly higher in gp91phox-/- mice. These results led to our hypothesis that gp91phox, through regulating MΦ efferocytosis, plays a critical role in the programming of tissue- restorative hepatic MΦ s, thereby protecting the liver from ALD. We propose two Specific Aims to examine this hypothesis: (Aim 1), Investigate the protective role of gp91phox in ethanol-induced liver inflammation and injury. The degrees of liver injury and inflammation will be compared between WT and gp91phox-/- mice in two models of ALD. Furthermore, bone marrow chimera experiments will be performed to elucidate the contribution of hepatic MΦs to the increased susceptibility of gp91phox-/- mice to ALD. (Aim 2), Investigate the impact of gp91phox-deletion on efferocytosis-induced programming of hepatic MΦs. Various subpopulations of MΦs will be isolated from the livers of ethanol-fed WT and gp91phox-/- mice. The gene profiles of each population will be compared between the two strains of mice. Moreover, the efferocytosis ability and the impact of efferocytosis on the cell phenotype will be compared in each hepatic MΦ population from WT and gp91phox-/- mice.

 描述（由适用提供）：酒精性肝病（ALD）影响美国超过1000万人，占肝硬化相关死亡的几乎一半。对疾病的发病机理的更好理解对于开发新疗法是必要的，这些疗法目前非常有限。先天免疫抑制系统在ALD的发病机理中起重要作用。巨噬细胞（Mφ）是先天免疫的主要细胞，并且在许多慢性炎症性疾病中已成为关键参与者和治疗靶标。有证据表明，肝脏MφS在ALD的发展和发展中很重要。在患者和动物模型中，在ALD的所有阶段都发现了肝脏Mφ数量的增加，并且表明Mφ激活的因素升高。肝脏MφS是具有潜水表型和功能的异质种群。除了居民Kupffer细胞（KCS）外，我们最近发现，向小鼠进食的慢性乙醇会引起肝脏浸润MφS（IMS）的肝募集，该浸润由促炎的Ly6CHI子集和抗炎，抗炎，组织性的Ly6clow子集组成。死细胞的吞噬作用（效应）促进了ly6chi ims向ly6clow ims的转换。此外，我们发现来自GP91Phox - / - 小鼠的肝脏Mφs损害了胞吞作用能力。有趣的是，与乙醇喂养的WT小鼠相比，在GP91Phox - / - 小鼠中，LY6CHI/LY6CLOW IMS以及肝损伤程度的比率明显更高。这些结果导致了我们的假设，即通过调节的Mφ吞噬作用，GP91Phox在组织恢复性肝MφS的编程中起着至关重要的作用，从而保护了肝脏免受ALD的侵害。我们提出了两个特定的目的来研究这一假设：（目标1），研究GP91Phox在乙醇诱导的肝感染和损伤中的保护作用。在两种ALD模型中，将比较WT和GP91Phox - / - 小鼠之间的肝损伤和感染程度。此外，将进行骨髓嵌合体实验，以阐明肝脏MφS对GP91Phox - / - 小鼠对ALD的敏感性增加的贡献。 （AIM 2），研究GP91Phox-Deotion对肝脏诱导的肝M或编程的影响。 MφS的各种亚群将从乙醇喂养的WT和GP91Phox - / - 小鼠的生活中分离出来。将在两种小鼠菌株之间比较每个种群的基因谱。此外，将比较来自WT和GP91Phox的每个肝M或小鼠中的每个肝M或小鼠的肝细胞增多症和肿瘤性肿瘤对细胞表型的影响。