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

基本信息

  • 批准号:
    10658560
  • 负责人:
  • 金额:
    $ 36.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)是非酒精性脂肪性肝病(NAFLD)的一种侵袭性形式, 其特征在于肝脂质积聚、肝损伤、炎症和纤维化。NASH的患病率 在过去的十年中急剧上升,使其成为肝脏相关发病率和死亡率的主要原因 这是世界范围内肝移植的主要原因。饮食性肥胖是NAFLD的触发因素, 肝脏中脂质过度积聚,导致肝细胞死亡,随后释放宿主来源的 损伤相关的分子模式,进而激活肝脏巨噬细胞引发肝脏炎症。等 炎症的特征在于促炎细胞因子(包括TNF、IL-6和IL-1b)的慢性产生。 过去十年的几项里程碑式的研究共同表明,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 在肝脏中建立慢性炎症仍然是难以捉摸的。最近,多个单细胞转录组 研究揭示了在髓样细胞2(TREM 2)表达中表达的触发受体的出现, 在NASH、肝硬化和肝细胞癌患者中高度富集的巨噬细胞群体。 为了研究巨噬细胞TREM 2在NASH发病机制中的作用,我们产生了骨髓细胞特异性Trem 2。 敲除小鼠,并使它们经受西方饮食诱导的NASH模型。我们发现巨噬细胞 TREM 2保护小鼠免受NASH发展。值得注意的是,我们意外地发现,尽管它的mRNA 在NASH进展过程中持续上调,TREM 2蛋白仅在单纯性脂肪变性中增加, 差点在NASH被淘汰我们进一步证明了NASH中TREM 2蛋白的急剧下降, 是由于存在于巨噬细胞表面上的全长TREM 2的蛋白水解裂解。本报告的总体目标 建议全面研究(1)在NASH致病过程中TREM 2表达如何调节 进展,(2)TREM 2在巨噬细胞中限制NASH发展的作用,以及(3)是否阻断 TREM 2切割可以抑制NASH进展。为实现这一目标,我们将采取以下三项具体措施: 目标。在目标1中,我们将破译TREM 2在细胞周期中动态调节的分子机制。 NASH进展。具体来说,我们将确定负责TREM 2上升和下降的关键信号通路, 分别在单纯脂肪变性和NASH阶段进行调节。在Aim 2中,我们将测试TREM 2是否扮演一个关键角色 在载脂凋亡肝细胞的巨噬细胞吞噬作用中的作用,从而限制慢性肝硬化 炎症和NASH发展。最后,在目的3中,通过利用抗切割Trem 2敲入(Trem 2 - 1000), 在IPD)小鼠中,我们将进行概念验证体内测试以确定阻断TREM 2切割是否能恢复TREM 2的表达。 巨噬细胞吞噬作用可抑制NASH。这项研究的完成不仅将提供急需的 机制的见解解释了长期营养过剩如何导致慢性肝脏炎症,但也将 为设计抗TREM 2切割方法治疗NASH奠定了坚实的基础。

项目成果

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Shuang Liang其他文献

Shuang Liang的其他文献

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{{ truncateString('Shuang Liang', 18)}}的其他基金

Treg regulation and its role in gingival inflammation during pregnancy (Administrative Supplements)
Treg 调节及其在妊娠期牙龈炎症中的作用(行政补充)
  • 批准号:
    9237746
  • 财政年份:
    2016
  • 资助金额:
    $ 36.08万
  • 项目类别:

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