Immunopathogenesis of non-alcoholic fatty liver disease

非酒精性脂肪肝的免疫发病机制

• 批准号: 10427752
• 负责人: Senad Divanovic
• 金额: $ 6.78万
• 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/10427752
• 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; Fatty Liver; 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; Liver diseases; 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; 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.

总结 有增无减的肥胖症大流行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）。免疫系统提供了一个关键的致病环节 肥胖和NAFLD发病机制之间的联系。白细胞介素（IL）17轴的激活是NAFLD的关键因素 进展考虑到靶向NAFLD致病性免疫应答的治疗前景， 对IL-17轴依赖性致病性的细胞和分子机制的理解是很高的， 要务在NAFLD中，Th 17细胞是IL-17 A的主要肝脏生产者。虽然Th 17细胞的异质性 炎症性疾病严重程度、独有的细胞特征和肝细胞功能的已知决定因素， Th 17细胞在NAFLD中尚未被研究。在这里，我们证明了NAFLD的进展与 一个独特的炎症性肝脏Th 17细胞亚群（ihTh 17）的积累，表现出代谢，表观遗传， 与常规肝Th 17细胞（chTh 17）和炎性Th 17细胞不同的转录特征 在EAE和克罗恩病的小鼠模型中观察到的Th 17细胞。我们令人兴奋的初步数据，在小鼠中， 表明：（i）肥胖相关的微生物组调节ihTh 17细胞活化;（ii）CXCR 3轴调节 ihTh 17诱导的NAFLD发病机制;和（iii）ihTh 17细胞足以加剧NAFLD进展 高于chTh 17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， NASH患者表现出增加的CXCR 3轴活化和ihTh 17细胞的肝浸润。我们一起， 研究结果和现有文献强烈支持肥胖驱动的肝脏蓄积的中心假设， ihTh 17细胞在NAFLD的发病机制中至关重要。我们的过度假设将通过 设计的目标将：（1）确定导致NAFLD中ihTh 17出现的因素;（2）确定 CXCR 3轴对NAFLD中ihTh 17肝脏累积的贡献;以及（3）确定CXCR 3轴对NAFLD中ihTh 17肝脏累积的贡献。 细胞代谢与ihTh 17炎症活性和NAFLD发病机制的关系。相关机制假说 这些目标分别是：（a）肥胖相关的炎症和微生物环境形状 （B）ihTh 17细胞的CXCR 3表达和ihTh 17细胞的CXCL 10表达; 肝细胞促进ihTh 17的肝积累;和（c）PKM 2驱动的糖酵解促进ihTh 17细胞因子的产生 并加重NAFLD发病机制。因此，我们提出的研究将提供新的知识， 在实验性NAFLD中许可ihTh 17致病潜力的未探索的细胞和分子过程， 它们在人类疾病中的参与程度。由于NAFLD的治疗缺乏，对IL-17轴的新见解- 依赖性致病机制具有发现新的预测、预防和治疗的潜力 大道。