Immunopathogenesis of non-alcoholic fatty liver disease

非酒精性脂肪肝的免疫发病机制

• 批准号: 10450163
• 负责人: Senad Divanovic
• 金额: $ 55.44万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450163
• 关键词: Adoptive Transfer; Antibiotic Therapy; Antibodies; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cell Lineage; Cells; Cellular Metabolic Process; Characteristics; Clinical; Coculture Techniques; Coupled; Crohn' s disease; Data; Dependence; Development; Diet; Disease Progression; Environment; Enzymes; Epigenetic Process; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; Extrahepatic; Funding; Gender; Gene Expression Profile; Genetic Transcription; Glycolysis; Goals; Hepatic; Hepatocellular Damage; Hepatocyte; Heterogeneity; Housing; Human; Immune; Immune response; Immune system; Immunohistochemistry; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Interleukin Activation; Interleukin-17; Interleukins; Knowledge; Licensing; Ligands; Link; Literature; Liver; Mediating; Metabolic; Metabolism; Molecular; Mus; Obesity; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Patients; Phenotype; Population; Preventive; Process; Production; Publishing; Pyruvate Kinase; Reporting; Research; Severities; Severity of illness; Shapes; System; T-Cell Activation; Temperature; Testing; Therapeutic; Western World; cell type; chronic liver disease; clinically relevant; cytokine; design; fatty liver disease; human disease; insight; liver biopsy; metabolome; microbiome; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; pandemic disease; programs; transcriptome

SUMMARY The unabated obesity pandemic drives dramatic increases in the incidence of common metabolic derangements including non-alchoholic fatty liver disease (NAFLD). The immune system provides a critical causative link between obesity and NAFLD pathogenesis. Activation of the interleukin (IL) 17 axis is a key contributor to NAFLD progression. Given the therapeutic promise for targeting pathogenic immune responses in NAFLD, enhanced understanding of the cellular and molecular mechanisms underlying IL-17 axis-dependent pathogenicity is a high priority. In NAFLD, Th17 cells are the primary hepatic producers of IL-17A. Although Th17 cell heterogeneity is a known determinant of inflammatory disease severity, exclusive cellular characteristics and function of hepatic Th17 cells in NAFLD have not been studied. Here, we demonstrate that NAFLD progression correlates with accrual of a unique inflammatory hepatic Th17 cell subset (ihTh17) that exhibits metabolic, epigenetic, and transcriptional signatures distinct from the conventional hepatic Th17 cells (chTh17) and from the inflammatory Th17 cells observed in mouse models of EAE and Crohn’s disease. Our exciting preliminary data, in mice, further suggest that: (i) obesity-associated microbiome regulates ihTh17 cell activation; (ii) the CXCR3 axis regulates ihTh17-induced NAFLD pathogenesis; and (iii) ihTh17 cells are sufficient to exacerbate NAFLD progression above the level induced by chTh17 cells. Importantly, these findings are recapitulated in human disease where NASH patients exhibit increased CXCR3 axis activation and hepatic infiltration of ihTh17 cells. Together, our findings and existing literature strongly support the central hypothesis that obesity-driven hepatic accrual of ihTh17 cells is critical to the pathogenesis of NAFLD. Our overaching hypothesis will be tested via intently designed aims that will: (1) Determine the factors contributing to ihTh17 emergence in NAFLD; (2) Determine the contribution of the CXCR3 axis to ihTh17 hepatic accrual in NAFLD; and (3) Determine the contribution of cellular metabolism to ihTh17 inflammatory vigor and NAFLD pathogenesis. Mechanistic hypotheses associated with these aims, respectively, are: (a) the obesity-associated inflammatory and microbiome environment shape the emergence of ihTh17 cell phenotype; (b) CXCR3 expression by ihTh17 cells and CXCL10 expression by hepatocytes promotes ihTh17 hepatic accrual; and (c) PKM2-driven glycolysis fuels ihTh17 cytokine production and exacerbates NAFLD pathogenesis. Thus, our proposed studies will provide new knowledge into previously unexplored cellular and molecular processes licensing ihTh17 pathogenic potential in experimental NAFLD and the extent of their involvement in human disease. As therapies to NAFLD are lacking, new insights to IL-17 axis- dependent pathogenic mechanisms hold potential for discovery of novel predictive, preventive and therapeutic avenues.

概括 肥胖流行趋势有增无减，导致常见代谢紊乱的发病率急剧增加 包括非酒精性脂肪肝（NAFLD）。免疫系统提供了关键的因果关系 肥胖与 NAFLD 发病机制之间的关系。白介素 (IL) 17 轴的激活是 NAFLD 的关键因素 进展。鉴于针对 NAFLD 致病性免疫反应的治疗前景，增强 对 IL-17 轴依赖性致病性的细胞和分子机制的了解是一个高度的了解 优先事项。在 NAFLD 中，Th17 细胞是 IL-17A 的主要肝脏生产者。尽管 Th17 细胞异质性 炎症性疾病严重程度、独特的细胞特征和肝功能的已知决定因素 尚未研究 NAFLD 中的 Th17 细胞。在这里，我们证明 NAFLD 进展与 独特的炎症性肝 Th17 细胞亚群 (ihTh17) 的积累，表现出代谢、表观遗传和 转录特征不同于传统的肝 Th17 细胞 (chTh17) 和炎症细胞 在 EAE 和克罗恩病小鼠模型中观察到的 Th17 细胞。我们在小鼠中的令人兴奋的初步数据进一步 表明：(i) 肥胖相关微生物组调节 ihTh17 细胞激活； (ii) CXCR3轴调节 ihTh17 诱导的 NAFLD 发病机制； (iii) ihTh17 细胞足以加剧 NAFLD 进展 高于 chTh17 细胞诱导的水平。重要的是，这些发现在人类疾病中得到了重现，其中 NASH 患者表现出 CXCR3 轴激活增加和 ihTh17 细胞肝浸润增加。在一起，我们的 研究结果和现有文献强烈支持这一中心假设：肥胖驱动的肝脏累积 ihTh17 细胞对于 NAFLD 的发病机制至关重要。我们的总体假设将通过仔细的测试 设计目标将： (1) 确定导致 NAFLD 中 ihTh17 出现的因素； (2)确定 CXCR3 轴对 NAFLD 中 ihTh17 肝脏累积的贡献； (3) 确定贡献 细胞代谢对 ihTh17 炎症强度和 NAFLD 发病机制的影响。相关的机制假说 这些目标分别是：（a）与肥胖相关的炎症和微生物组环境形状 ihTh17细胞表型的出现； (b) ihTh17 细胞的 CXCR3 表达和 CXCL10 的表达 肝细胞促进 ihTh17 肝脏生成； (c) PKM2 驱动的糖酵解促进 ihTh17 细胞因子的产生 并加剧 NAFLD 的发病机制。因此，我们提出的研究将为以前的研究提供新的知识 未探索的细胞和分子过程许可 ihTh17 在实验性 NAFLD 和 它们与人类疾病的关系程度。由于缺乏 NAFLD 的治疗方法，对 IL-17 轴的新见解- 依赖的致病机制具有发现新的预测、预防和治疗方法的潜力 途径。