Dissecting the Intracellular and Extracellular Role of TREM2 in the Pathogenesis of Non-Alcoholic Steatohepatitis.

摘要： 非酒精性脂肪性肝炎（NASH）是美国肝癌和肝移植增长最快的原因。 目前尚无获批的NASH治疗方法， 脂肪肝患者保持良性状态，而其他人进展为NASH尚不清楚。宏观经济发挥作用 在NASH发病机制中起关键作用。越来越多的证据表明，“触发受体表达在 在NASH相关巨噬细胞中，“骨髓细胞”（TREM 2）过表达。有趣的是，即使TREM 2 当在NASH期间表达增加时，其缺乏会加剧NASH和纤维化发展。这表明 TREM 2在NASH和纤维化进展中具有保护作用。然而，TREM 2信号传导的机制 仍然知之甚少。 此外，在配体接合时，TREM 2从细胞表面裂解成可溶性形式（sTREM 2）。 可以在血清中检测到我们发现sTREM 2水平随着NAFLD和NASH进展而增加， 然而，sTREM 2的反式信号传导轴是本领域尚未解决的领域。sTREM2 具有吸收炎性配体如LPS和脂质以及结合巨噬细胞的能力。然而，在这方面， sTREM 2是否可以结合并影响其他细胞中的下游信号传导仍然是未知的。我们发现 sTREM 2本身具有NASH保护和治疗能力。将sTREM 2片段引入 已经患有晚期NASH的小鼠对NASH和纤维化消退具有深远的影响。 该提案的目标是更好地了解TREM 2如何发挥其保护功能，并分析TREM 2的作用机制。 TREM 2的细胞内和反式信号传导轴。 我们将使用NASH和HCC的小鼠模型，其密切模拟饮食诱导的代谢综合征和人类的代谢综合征。 NASH基因标记以及小鼠和人肝细胞的原代培养物，以评估NASH基因标记的表达。 以下2个具体目标：目标1将确定发挥其作用的关键细胞内TREM 2信号通路。 控制NASH发展的保护措施。我们还将确定负责转录因子 NASH相关巨噬细胞中的TREM 2表达。目的2将阐明的反式信号的性质， sTREM 2以及sTREM 2是否直接参与疾病进展。拟议的研究将提供 NASH和HCC发展机制的关键见解。这项研究的结果将奠定 为将来开发和完善sTREM 2作为NASH-纤维化的新型治疗剂奠定了基础 和HCC。

Abstract: Non-alcoholic steatohepatitis (NASH) is the fastest growing cause of liver cancer and liver transplant in the U.S. There is currently no approved treatment for NASH and the mechanistic understanding of why some patients with fatty liver maintain a benign condition while others progress to NASH is not clear. Macrophages play a pivotal role in NASH pathogenesis. Accumulating evidence suggest that ‘triggering receptor expressed on myeloid cells’ (TREM2) is overexpressed in NASH associated macrophages. Interestingly, even though TREM2 expression is increased during NASH, its absence exacerbates NASH and fibrosis development. This indicates that TREM2 is protective in NASH and fibrosis progression. However, the mechanism of TREM2 signaling remains poorly understood. Moreover, upon ligand engagement, TREM2 gets cleaved from the cell surface into a soluble form (sTREM2) that can be detected in the serum. We found that sTREM2 levels increase with NAFLD and NASH progression, however, the trans-signaling axis of sTREM2 is an area that has not been addressed in the field yet. sTREM2 has the ability to soak up inflammatory ligands such as LPS and lipids as well as bind to macrophages. However, whether sTREM2 can bind and influence downstream signaling in other cells remain unknown. We discovered that sTREM2 itself has NASH protective as well as therapeutic abilities. Introduction of sTREM2 fragment into mice that already had advanced NASH had profound effects on NASH and fibrosis resolution. The goal of this proposal is to better understand how TREM2 exerts its protective functions and dissect the intracellular and trans-signaling axes of TREM2. We will use mouse models of NASH and HCC that closely mimics diet induced metabolic syndrome and human NASH gene signature as well as primary cultures of both mouse and human liver cells in order to assess the following 2 Specific Aims: Aim 1 will identify the key intracellular TREM2 signaling pathways that exerts its protective actions in controlling NASH development. We will also identify the transcription factors responsible for TREM2 expression in NASH associated macrophages. Aim 2 will elucidate the trans-signaling properties of sTREM2 and whether sTREM2 is directly involved in disease progression. The proposed studies will provide key insights into the mechanisms of NASH and HCC development. The findings from this study will lay the foundation for future development and refinement of sTREM2 as a novel therapeutic agent for NASH-Fibrosis and HCC.