Targeting mononuclear phagocytes development in alcohol induced liver damage: pathological and immunological pathways

酒精性肝损伤中单核吞噬细胞的发育：病理学和免疫学途径

• 批准号: 9766987
• 负责人: Costica Aloman
• 金额: $ 35.33万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/9766987
• 关键词: Affect; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Asses; Bacterial Translocation; Blood; Bone Marrow; Bone Marrow Transplantation; CCL2 gene; Cell Adhesion Molecules; Cell Lineage; Characteristics; Chronic; Clinical; Complex; Data; Defect; Dendritic Cells; Development; Diet; Disease; Down-Regulation; Endothelium; Enterobacteriaceae; Ethanol; Event; FLT3 ligand; Fatty Liver; Feedback; Fibrosis; Generations; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic; Hepatic; Homeostasis; Human; Immune; Immune response; Immune system; Immunologics; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Interleukin-1 beta; Interleukin-6; Intestinal permeability; Knowledge; Lead; Leukocytes; Liver; Liver Cirrhosis; Lymphoid; Macrophage Colony-Stimulating Factor; Maintenance; Marrow; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mononuclear; Morbidity - disease rate; Morphology; Mus; Natural Immunity; Neutrophil Infiltration; Organ; Outcome; Pathogenesis; Pathologic; Pathway interactions; Phagocytes; Phenotype; Population; Predisposition; Production; Regulation; Research; Research Project Grants; Resistance to infection; Role; Salmonella; Sepsis; Severities; Source; Stem cells; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Tissues; Toxic effect; Up-Regulation; adaptive immune response; adaptive immunity; alcohol effect; alcohol exposure; alcohol testing; base; bone; cellular targeting; chemokine; chronic alcohol ingestion; cytokine; cytotoxic; drinking water; improved; insight; liver injury; macrophage; monocyte; mortality; mouse model; neutrophil; new therapeutic target; novel; progenitor; response; trafficking; transcription factor

ABSTRACT Alcohol consumption causes a spectrum of clinical illness and morphological changes that range from fatty liver to hepatic inflammation (alcoholic hepatitis) and progressive fibrosis (alcoholic cirrhosis). Alcoholic liver disease has an incompletely known pathogenesis and specific treatments are lacking. It is an extremely common disease with significant mortality and morbidity. T cellular immune responses were shown to be affected and involved in these outcomes. Decreased resistance to infections and an abnormal systemic inflammatory response to infections are common events associated with alcohol consumption. Alcohol exposure has complex effects on gut permeability and the immune system, resulting in activation of mononuclear phagocytes, steatosis, neutrophil recruitment and altered cellular immune responses. Dendritic cells (DC), professional antigen presenting cells, are emerging as an important regulator of tissue microenvironment. After four decades of research, we now know that DC arise from a hematopoietic lineage distinct from other leukocytes (including monocytes and macrophages), establishing the DC lineage as a unique hematopoietic branch. Several DC populations coexist in mice and humans with similar developmental pathways: (1) conventional DC (cDC) involved in antigen presentation; (2) plasmacytoid DC (pDC), characterized by a high capacity of cytokine production. pDC development and maintenance is under control of a transcription factor: E2-2. pDC release from marrow is dependent of CCR2. These data, combined with our central preliminary observation showing increased hepatic pDC in a well-established model of chronic alcohol consumption, sparked the idea of a potential effect of alcohol on pDC development with accumulation of hepatic pDC that reshapes the hepatic pro-inflammatory cytokine milieu and results in abnormal T helper 1 and Th17 cellular immune responses known to be present after chronic alcohol consumption. Our long-term goal is to investigate the effects of alcohol on DC homeostasis and their effect on immune and pathological characteristics seen in alcoholic liver disease. Our central hypothesis is that alcohol induces abnormal DC development and hepatic pDC accumulation. The high cytokine production capacity of pDC stimulated by bacterial products reaching the liver may contribute to hepatic and blood TNFα production, a well-known central mediator of alcoholic liver injury. Further, pDC participate in increased generation of Th17 (well-known to be directly involved in promoting neutrophilic inflammation) and down-regulation of Th1 immune responses. We will test our central hypothesis through the following interrelated Specific Aims: (1) We will test whether alcohol consumption increases pDC release from bone marrow by increasing E2-2 dependent pDC development and their CCR2 dependent egress. (2) We will test if alcohol primes hepatic pDC for NFκB- mediated cytokine production, contributing to Th17 induction, defective Th1 response and increasing severity of infection with enteric bacteria.

摘要 饮酒会导致一系列临床疾病和形态学变化，从脂肪 肝脏炎症（酒精性肝炎）和进行性纤维化（酒精性肝硬化）。酒精性肝 疾病的发病机制尚不完全清楚，缺乏特异性治疗。这是一个极其 常见病，发病率和死亡率高。T细胞免疫反应显示， 影响和参与这些结果。对感染的抵抗力下降， 对感染的炎症反应是与饮酒相关的常见事件。醇 暴露对肠道渗透性和免疫系统有复杂的影响，导致 单核吞噬细胞、脂肪变性、中性粒细胞募集和改变的细胞免疫应答。树突状 细胞（DC）是专职的抗原呈递细胞，正在成为组织的重要调节者， 微环境经过40年的研究，我们现在知道DC起源于造血谱系， 与其他白细胞（包括单核细胞和巨噬细胞）不同，建立DC谱系作为一种免疫调节因子。 独特的造血分支。几个DC群体在小鼠和人类中共存，具有相似的发育 途径：（1）参与抗原呈递的常规DC（cDC）;（2）浆细胞样DC（pDC）， 其特征在于细胞因子产生的高能力。pDC的开发和维护由 转录因子：E2-2。从骨髓释放pDC依赖于CCR 2。这些数据，结合我们的 中心初步观察结果显示，在良好建立的慢性酒精模型中，肝脏pDC增加 消费，引发了酒精对pDC发育的潜在影响的想法， 肝脏pDC，重塑肝脏促炎细胞因子环境并导致异常T辅助细胞1， Th 17细胞免疫反应已知存在于慢性饮酒后。 我们的长期目标是研究酒精对DC稳态的影响以及它们对 酒精性肝病的免疫和病理特征。我们的核心假设是酒精 诱导异常DC发育和肝pDC积累。细胞因子的高生产能力 到达肝脏的细菌产物刺激的pDC可能有助于肝脏和血液TNFα的产生， 一种众所周知的酒精性肝损伤的中枢介质。此外，pDC参与增加的Th 17产生 （众所周知直接参与促进嗜中性炎症）和下调Th 1免疫调节 应答我们将通过以下相互关联的具体目标来检验我们的中心假设：（1）我们将检验 饮酒是否通过增加E2-2依赖性pDC来增加骨髓中pDC的释放 发展和它们的CCR 2依赖性出口。(2)我们将测试酒精是否为NFκB启动肝脏pDC- 介导的细胞因子产生，导致Th 17诱导、Th 1应答缺陷和严重程度增加 肠道细菌感染的症状