Deciphering the role of TREM2 in Non-Alcoholic Steatohepatitis

解读 TREM2 在非酒精性脂肪性肝炎中的作用

• 批准号: 10658560
• 负责人: Shuang Liang
• 金额: $ 36.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658560
• 关键词: Acceleration; Amino Acid Substitution; Apoptotic; Automobile Driving; Back; Biological Process; Cells; Cessation of life; Chronic; Cirrhosis; Data; Defect; Development; Down-Regulation; Event; Exhibits; Fatty Liver; Fibrosis; Foundations; Gatekeeping; Genetic; Goals; Hepatic; Hepatocyte; High Fat Diet; Inflammation; Inflammatory; Interleukin-6; Knock-in; Knock-in Mouse; Knockout Mice; Kupffer Cells; Length; Licensing; Lipids; Liver; Macrophage; Mediating; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Obesity; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phagocytes; Phagosomes; Phenotype; Play; Population; Prevalence; Primary carcinoma of the liver cells; Process; Production; Proteins; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Site; Surface; TNF gene; TREM2 gene; Testing; Up-Regulation; chronic liver disease; chronic liver inflammation; combat; cytokine; design; dietary; experimental study; feeding; hepatocyte injury; in vivo; in vivo evaluation; inorganic phosphate; insight; liver inflammation; liver injury; liver transplantation; mortality; mouse model; mutant; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutic intervention; novel therapeutics; overexpression; preservation; prevent; simple steatosis; therapy development; transcriptome sequencing; transcriptomics; western diet

Project Summary Nonalcoholic steatohepatitis (NASH), an aggressive form of nonalcoholic fatty liver disease (NAFLD), is characterized by hepatic lipid buildup, liver damage, inflammation, and fibrosis. The prevalence of NASH has skyrocketed during the past decade, making it the leading cause of liver-related morbidity and mortality worldwide and a primary reason for liver transplantation. Dietary obesity, the trigger of NAFLD, induces excessive lipid accumulation in the liver, causing hepatocyte death and subsequent release of host-derived damage-associated molecular patterns that in turn activate liver macrophage to ignite hepatic inflammation. Such inflammation is featured by chronic production of proinflammatory cytokines, including TNF, IL-6, and IL-1b. Several landmark studies in the past decade have collectively shown that chronic liver inflammation is the key switch mediating simple steatosis transition into NASH. However, how dietary obesity promotes the establishment of chronic inflammation in the liver remains elusive. Recently, multiple single-cell transcriptomic studies revealed the emergence of a triggering receptor expressed in myeloid cell 2 (TREM2)-expressing macrophage population that is highly enriched in patients with NASH, cirrhosis and hepatocellular carcinoma. To study the role of macrophage TREM2 in NASH pathogenesis, we generated myeloid cell-specific Trem2 knockout mice and subjected them to a western diet-induced NASH model. We discovered that macrophage TREM2 protects mice against NASH development. Of note, we unexpectedly found that despite its mRNA being continuously upregulated throughout NASH progression, TREM2 protein only increases in simple steatosis but almost gets eliminated at NASH. We further demonstrated that the dramatic decline of TREM2 protein in NASH is due to proteolytic cleavage of full-length TREM2 present on macrophage surface. The overall objective of this proposal is to comprehensively investigate (1) how TREM2 expression is regulated during NASH pathogenic progression, (2) what TREM2 does in macrophages to restrict NASH development, and (3) whether blocking TREM2 cleavage can inhibit NASH progression. To achieve this goal, we will pursue the following three specific aims. In Aim 1, we will decipher the molecular mechanism by which TREM2 is dynamically regulated during NASH progression. Specifically, we will identify key signaling pathways responsible for TREM2 up- and down- regulation at simple steatosis and NASH stages, respectively. In Aim 2, we will test whether TREM2 plays a key role in macrophage efferocytosis of lipid-laden apoptotic hepatocytes and thereby restrict chronic liver inflammation and NASH development. Lastly, in Aim 3, by utilizing a cleavage-resistant Trem2 knock-in (Trem2- IPD) mice, we will perform a proof-of-concept in vivo test to determine if blocking TREM2 cleavage to restore macrophage efferocytosis can inhibit NASH. Completion of this study will not only provide much-needed mechanistic insights explaining how prolonged hypernutrition results in chronic liver inflammation, but also will establish a concrete foundation for designing anti TREM2 cleavage approaches to treat NASH.

项目概要 非酒精性脂肪性肝炎 (NASH) 是非酒精性脂肪性肝病 (NAFLD) 的一种侵袭性形式， 其特征是肝脂质堆积、肝损伤、炎症和纤维化。 NASH 的患病率已 在过去十年中急剧上升，使其成为肝脏相关发病率和死亡率的主要原因 在世界范围内，这也是肝移植的主要原因。饮食肥胖是 NAFLD 的诱因，可诱发 肝脏中脂质过多积聚，导致肝细胞死亡并随后释放宿主源性物质 损伤相关的分子模式反过来激活肝脏巨噬细胞以引发肝脏炎症。这样的 炎症的特点是促炎细胞因子的长期产生，包括 TNF、IL-6 和 IL-1b。 过去十年的几项具有里程碑意义的研究共同表明，慢性肝脏炎症是关键 介导简单脂肪变性转变为 NASH 的开关。然而，饮食性肥胖如何促进 肝脏中慢性炎症的建立仍然难以捉摸。最近，多个单细胞转录组 研究揭示了表达骨髓细胞 2 (TREM2) 的触发受体的出现 NASH、肝硬化和肝细胞癌患者中高度富集的巨噬细胞群。 为了研究巨噬细胞 TREM2 在 NASH 发病机制中的作用，我们生成了骨髓细胞特异性 Trem2 基因敲除小鼠，并将其置于西方饮食诱导的 NASH 模型中。我们发现巨噬细胞 TREM2 可以保护小鼠免受 NASH 的发展。值得注意的是，我们意外地发现，尽管它的 mRNA 是 TREM2 蛋白在 NASH 进展过程中持续上调，仅在单纯性脂肪变性中增加，但 几乎在NASH被淘汰。我们进一步证明 TREM2 蛋白在 NASH 中的急剧下降 是由于巨噬细胞表面存在的全长 TREM2 的蛋白水解裂解所致。本次活动的总体目标 建议全面研究（1）NASH致病过程中TREM2的表达是如何调控的 (2) TREM2 在巨噬细胞中如何限制 NASH 的发展，以及 (3) 是否阻断 TREM2 裂解可以抑制 NASH 进展。为实现这一目标，我们将采取以下三项具体行动： 目标。在目标1中，我们将破译TREM2在过程中动态调节的分子机制。 NASH 进展。具体来说，我们将确定负责 TREM2 上调和下调的关键信号通路 分别在简单脂肪变性和 NASH 阶段进行调节。在目标2中，我们将测试TREM2是否发挥关键作用 在充满脂质的凋亡肝细胞的巨噬细胞胞吞作用中的作用，从而限制慢性肝 炎症和 NASH 的发展。最后，在目标 3 中，通过利用抗切割 Trem2 敲入（Trem2- IPD）小鼠，我们将进行体内概念验证测试，以确定阻断 TREM2 裂解是否可以恢复 巨噬细胞胞吞作用可以抑制NASH。这项研究的完成不仅将提供急需的 解释长期营养过剩如何导致慢性肝脏炎症的机制见解，但也将 为设计抗 TREM2 裂解方法治疗 NASH 奠定坚实的基础。