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（由申请人提供）：酒精性肝病（ALD）影响美国超过1000万人，占肝硬化相关死亡的近一半。更好地了解疾病的发病机制是必要的，以开发新的治疗方法，这是目前相当有限的。先天免疫系统在ALD的发病机制中起重要作用。巨噬细胞（MΦ）是天然免疫的主要细胞类型，并且已经成为许多慢性炎症性疾病的关键参与者和治疗靶点。有证据表明肝脏MΦ在ALD的发生和发展中起重要作用。在患者和动物模型中，在ALD的所有阶段都发现肝脏MΦ数量增加，并且指示MΦ活化的因子升高。肝脏MΦ是具有不同表型和功能的异质性群体。除了常驻库普弗细胞（KC）之外，我们最近发现，对小鼠的慢性乙醇喂养引起浸润性MΦ（IM）的肝脏募集，其由促炎性Ly 6Chi亚群和抗炎性组织保护性Ly 6Clw亚群组成。死亡细胞的吞噬作用（吞噬细胞作用）促进Ly 6Chi IM向Ly 6Clow IM的转换。此外，我们还发现gp 91 phox-/-小鼠的肝脏MΦ具有受损的吞噬能力。有趣的是，与乙醇喂养的WT小鼠相比，Ly 6Chi/Ly 6Clow IM的比率以及肝损伤的程度在gp 91 phox-/-小鼠中显著更高。这些结果导致我们的假设，即gp 91 phox通过调节MΦ胞浆细胞增多，在组织恢复性肝MΦ的编程中起关键作用，从而保护肝脏免受ALD。我们提出了两个具体的目的来验证这一假设：（目的1），研究gp 91 phox在乙醇诱导的肝脏炎症和损伤中的保护作用。将在两种ALD模型中比较WT和gp 91 phox-/-小鼠之间的肝损伤和炎症程度。此外，将进行骨髓嵌合体实验以阐明肝MΦs对gp 91 phox-/-小鼠对ALD的易感性增加的贡献。(Aim 2）研究gp 91 phox基因缺失对巨噬细胞诱导的肝MΦ编程的影响。将从乙醇喂养的WT和gp 91 phox-/-小鼠的肝脏中分离MΦ的各种亚群。将在两种小鼠品系之间比较每个种群的基因谱。此外，将在来自WT和gp 91 phox-/-小鼠的每个肝MΦ群体中比较巨噬细胞能力和巨噬细胞对细胞表型的影响。