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: 10240584
• 负责人: Costica Aloman
• 金额: $ 31.79万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240584
• 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; 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; Interferon Type I; Interleukin-1 beta; Interleukin-6; Intestinal permeability; Knowledge; Lead; Leukocytes; Liver; Liver Cirrhosis; 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; Outcome; Pathogenesis; Pathologic; Pathway interactions; Phagocytes; Phenotype; Population; Predisposition; Production; Regulation; Research; Research Project Grants; Resistance to infection; Role; Salmonella; Sepsis; Severities; Source; 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; primary lymphoid organ; progenitor; response; stem cells; systemic inflammatory response; tissue injury; 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变化，从肥胖到肥胖 肝脏至肝脏炎症(酒精性肝炎)和进行性纤维化(酒精性肝硬变)。酒精性肝 该病的发病机制尚不完全清楚，缺乏具体的治疗方法。它是一种极端的 具有显著死亡率和发病率的常见病。T细胞免疫反应被证明是 影响并参与了这些结果。对感染的抵抗力下降和异常的全身 对感染的炎症反应是与饮酒有关的常见事件。酒精 暴露对肠道通透性和免疫系统有复杂的影响，导致激活 单核吞噬细胞、脂肪变性、中性粒细胞募集和细胞免疫反应改变。树枝状 细胞(DC)是一种专职的抗原提呈细胞，是组织的重要调节细胞。 微环境。经过40年的研究，我们现在知道DC起源于一种造血系 与其他白细胞(包括单核细胞和巨噬细胞)不同，DC谱系是 独特的造血支。多个DC群体在小鼠和人类体内共存，具有相似的发育 途径：(1)参与抗原提呈的常规DC(CDC)；(2)浆细胞样DC(PDC)； 以产生细胞因子的高能力为特征的。PDC的开发和维护受控于 转录因子：E2-2。PDC从骨髓释放依赖于CCR2。这些数据，与我们的 中枢初步观察显示慢性酒精模型肝脏PDC增加 饮酒，引发了酒精对PDC发展的潜在影响的想法，因为酒精积累了 肝脏PDC重塑肝脏促炎细胞因子环境并导致T辅助细胞1和 已知的长期饮酒后存在的细胞免疫反应。 我们的长期目标是研究酒精对DC动态平衡的影响及其对 酒精性肝病的免疫和病理特征。我们的中心假设是酒精 导致DC发育异常和肝脏PDC蓄积。细胞因子的高生产能力 细菌产物刺激的pDC到达肝脏可能有助于肝脏和血液中肿瘤坏死因子α的产生， 是众所周知的酒精性肝损伤的中枢调节因子。此外，PDC还参与了增加Th17的生成 (众所周知直接参与促进中性粒细胞炎症)和下调Th1免疫 回应。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 饮酒是否通过增加依赖E2-2的PDC而增加骨髓PDC的释放 发展及其依赖CCR2的出口。(2)我们将测试酒精是否能刺激肝脏pDC中的核因子κB- 介导的细胞因子的产生，有助于Th17的诱导，Th1反应的缺陷和严重性的增加 感染肠道细菌的可能性。

项目成果

Environmental exposures are important risk factors for advanced liver fibrosis in African American adults.

• DOI: 10.1016/j.jhepr.2023.100696
• 发表时间: 2023-04
• 期刊: JHEP REPORTS
• 影响因子: 8.3
• 作者: Ma, Ning;Yip, Rowena;Lewis, Sara;Dinani, Amreen;Wyatt, Christina;Crane, Michael;Jirapatnakul, Artit;Li, Li;Aloman, Costica;Bansal, Meena B.;Dieterich, Douglas;Wyatt, Brooke;Yankelevitz, David;Henschke, Claudia;Branch, Andrea D.
• 通讯作者: Branch, Andrea D.

Alcohol Consumption Accumulation of Monocyte Derived Macrophages in Female Mice Liver Is Interferon Alpha Receptor Dependent.

• DOI: 10.3389/fimmu.2021.663548
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Alharshawi K;Fey H;Vogle A;Klenk T;Kim M;Aloman C
• 通讯作者: Aloman C

Sex specific effect of alcohol on hepatic plasmacytoid dendritic cells.

• DOI: 10.1016/j.intimp.2020.107166
• 发表时间: 2021-01
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Alharshawi K;Fey H;Vogle A;Klenk T;Kim M;Aloman C
• 通讯作者: Aloman C

Murine Models of Alcohol Consumption: Imperfect but Still Potential Source of Novel Biomarkers and Therapeutic Drug Discovery for Alcoholic Liver Disease.

饮酒的鼠模型：新型生物标志物和酒精性肝病的治疗药物发现的不完善但仍有潜在的来源。

• DOI: 10.33696/immunology.3.096
• 发表时间: 2021
• 期刊: Journal of cellular immunology
• 作者: Alharshawi K;Aloman C
• 通讯作者: Aloman C

Differential expression of hepatic cancer stemness and hypoxia markers in residual cancer after locoregional therapies for hepatocellular carcinoma.

肝细胞癌局部疗法后，残留癌症中肝癌干和缺氧标记的差异表达。

• DOI: 10.1002/hep4.2079
• 发表时间: 2022-11
• 期刊: Hepatology communications
• 影响因子: 5.1