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.

项目摘要 非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪肝病（NAFLD）的侵略性形式，是 其特征是肝脂质堆积，肝损伤，炎症和纤维化。纳什的患病率 在过去的十年中飙升，使其成为与肝有关的发病率和死亡率的主要原因 全球和肝移植的主要原因。饮食肥胖，NAFLD的触发器，引起 肝脏中过多的脂质积聚，导致肝细胞死亡并随后释放宿主衍生 损伤相关的分子模式又激活了肝巨噬细胞以点燃肝发炎。这样的 炎症的特征是促炎细胞因子的长期产生，包括TNF，IL-6和IL-1B。 在过去十年中，几项具有里程碑意义的研究统一表明，慢性肝脏炎症是关键 切换简单的脂肪变化过渡到纳什。但是，饮食肥胖如何促进 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 研究揭示了在表达髓样细胞2（trem2）中表达的触发受体的出现 巨噬细胞种群高度富含NASH，肝硬化和肝细胞癌患者。 为了研究巨噬细胞Trem2在NASH发病机理中的作用，我们产生了髓样细胞特异性Trem2 敲除小鼠，并使它们接受了西方饮食引起的NASH模型。我们发现巨噬细胞 TREM2保护小鼠免受纳什的发展。值得注意的是，我们出乎意料地发现，尽管它的mRNA是 在整个NASH进展过程中，不断上调，Trem2蛋白仅在简单的脂肪变性中增加，但 纳什几乎被淘汰。我们进一步证明了NASH中TREM2蛋白的急剧下降 是由于巨噬细胞表面上存在的全长TREM2的蛋白水解裂解。总体目标 提案是为了全面研究（1）在NASH致病期间如何调节TREM2的表达 进展，（2）TREM2在巨噬细胞中所做的以限制纳什的发展，以及（3）是否阻止 TREM2裂解可以抑制NASH的进展。为了实现这一目标，我们将追求以下三个特定的特定 目标。在AIM 1中，我们将破译TREM2在此期间动态调节的分子机制 纳什的进展。具体而言，我们将确定负责Trem2上下负责的关键信号通路 在简单的脂肪变性和NASH阶段进行调节。在AIM 2中，我们将测试TREM2是否扮演钥匙 巨噬细胞的巨噬细胞衰减中脂质凋亡肝细胞的作用，从而限制慢性肝脏 炎症和纳什发育。最后，在AIM 3中，通过使用抗切割的Trem2敲入（TREM2-） ipd）小鼠，我们将执行体内测试概念验证，以确定是否阻止trem2裂解以恢复 巨噬细胞传染性细胞增多症可以抑制纳什。这项研究的完成不仅将提供急需的 机械洞察力解释了长时间的满足性如何导致慢性肝脏炎症，但也将 为设计抗TREM2裂解方法建立一个具体的基础来治疗NASH。