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) 在美国影响着超过 1000 万人，占肝硬化相关死亡人数的近一半，有必要更好地了解该疾病的发病机制，以开发新的疗法。目前，先天免疫系统在 ALD 的发病机制中发挥着重要作用，巨噬细胞 (MΦ) 是先天免疫细胞的主要类型，并已成为关键参与者。有证据表明，肝脏 MΦ 在 ALD 的发生和进展中发挥着重要作用，在 ALD 的各个阶段均发现肝脏 MΦ 数量增加，并且表明 MΦ 激活的因素。肝脏 MΦ 是一个具有不同表型和功能的异质群体，除了常驻库普弗细胞 (KC) 之外，我们最近发现，长期给小鼠喂食乙醇会导致肝脏招募 MΦ。浸润性 MΦ s (IMs)，由促炎性 Ly6Chi 子集和抗炎性、组织保护性 Ly6Clow 子集组成，死细胞的吞噬作用（胞吞作用）促进 Ly6Chi IMs 向 Ly6Clow IMs 的转换。 gp91phox-/- 小鼠的肝脏 MΦ 胞吞能力受损。乙醇喂养的 WT 小鼠中，gp91phox-/- 小鼠的 Ly6Chi/Ly6Clow IM 比率以及肝损伤程度显着较高。这些结果使我们假设 gp91phox 通过调节 MΦ 胞吞作用发挥着关键作用。我们两人提出了具体目标来检验这一假设： （目标1），研究gp91phox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gp91phox-/-小鼠的肝脏损伤和炎症程度。将进行以阐明肝脏 MΦ 对 gp91phox-/- 小鼠对 ALD 易感性增加的贡献（目标 2），研究 gp91phox 缺失对胞吞作用诱导的肝脏 MΦ 编程的影响将从乙醇喂养的 WT 和 gp91phox-/- 小鼠的肝脏中分离出各种 MΦ 亚群。将比较两个群体的基因谱。此外，将比较每种小鼠品系的胞吞能力以及胞吞作用对细胞表型的影响。来自 WT 和 gp91phox-/- 小鼠的肝脏 MΦ 群体。