Immunopathogenesis of non-alcoholic fatty liver disease

摘要 有增无减的肥胖大流行导致常见代谢紊乱的发生率急剧增加 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。 肥胖与NAFLD发病机制之间的关系。白细胞介素17轴的激活是NAFLD的关键因素 进步。鉴于NAFLD靶向致病免疫反应的治疗前景，增强了 对IL-17轴依赖致病的细胞和分子机制的理解是很高的 优先考虑。在NAFLD中，Th17细胞是肝脏产生IL-17A的主要细胞。尽管Th17细胞的异质性 已知的炎症性疾病严重程度的决定因素，独特的细胞特征和肝脏功能 NAFLD中的Th17细胞尚未被研究。在这里，我们证明了NAFLD的进展与 一种独特的炎症性肝脏Th17细胞亚群(IhTh17)的增加，表现为代谢、表观遗传和 转录特征不同于传统的肝脏Th17细胞(ChTh17)和炎性细胞 在EAE和克罗恩病小鼠模型中观察到Th17细胞。我们令人兴奋的初步数据，在老鼠身上，进一步 提示：(I)肥胖相关的微生物组调节ihTh17细胞的激活；(Ii)CXCR3轴调节 IhTh17诱导的NAFLD发病机制；以及(Iii)ihTh17细胞足以加剧NAFLD的进展 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概括 NASH患者表现为CXCR3轴激活增加，肝脏ihTh17细胞浸润。在一起，我们的 研究结果和现有文献有力地支持了这一中心假设，即肥胖导致的肝脏积聚 IhTh17细胞在NAFLD的发病机制中起关键作用。我们的过度使用假设将通过特意测试 设计的目的是：(1)确定导致非酒精性脂肪肝中ihTh17出现的因素；(2)确定 CXCR3轴对非酒精性脂肪肝ihTh17肝累积量的贡献；以及(3)确定 细胞代谢对ihTh17炎症活力与NAFLD发病机制的影响。相关的机械论假说 这些目标分别是：(A)与肥胖相关的炎症和微生物环境的形态 IhTh17细胞表型出现；(B)ihTh17细胞表达CXCR3； 肝细胞促进ihTh17肝脏增殖；和(C)PKM2驱动的糖酵解刺激ihTh17细胞因子的产生 并加重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致病潜力在实验性NAFLD和 他们参与人类疾病的程度。由于缺乏治疗NAFLD的方法，对IL-17轴的新见解- 依赖致病机制具有发现新的预测性、预防性和治疗性的潜力 林荫道。

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.