Lipid antigens as metabolic regulators of inflammation in non-alcoholic fatty liver disease

脂质抗原作为非酒精性脂肪肝炎症代谢调节剂

基本信息

项目摘要

Obesity shows a rising incidence worldwide and is associated with inflammatory and malignant complications. Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disorder associated with obesity and characterized by hepatocellular lipid accumulation. While NAFLD often shows a benign course of disease, hepatic steatosis can progress to an inflammatory state termed nonalcoholic steatohepatitis (NASH), which represents a risk factor for hepatic fibrosis and cirrhosis. Centrally involved in this process are natural killer T (NKT) cells, a subgroup of T cells which recognize lipid antigens in the context of the atypical MHC class I protein CD1d. However, while the role of NKT cells in the progression of NASH has been extensively characterized, the molecular nature of the antigens involved in NKT cell activation as well as their cellular origin remains unknown. Recent work has revealed that progression from steatosis to steatohepatitis in NAFLD is associated with increased hepatic abundance of lysophospholipids. Furthermore, we could demonstrate that CD1d-restricted presentation of lysophospholipids by hepatocytes is associated with the activation of hepatic NKT cells. We therefore propose to investigate whether metabolic alterations in NAFLD promote NKT cell-dependent inflammation in steatohepatitis through the generation of CD1d-associated lipid antigens. Given that CD1d is widely expressed among hepatic antigen presenting cells (APCs), we propose to first identify the APCs responsible for CD1d- and NKT cell-mediated hepatic inflammation in NASH using mice with conditional, cell-specific deletion of CD1d. Second, using human tissues and mice engineered to express a surface-cleavable form of CD1d, we propose to characterize, for the first time, the spectrum of lipids associated with hepatic CD1d in vivo and to identify alterations in the repertoire of CD1d-associated lipids that contribute to NKT cell-dependent progression of NAFLD. Third, we propose to investigate whether targeting of metabolic pathways involved in the generation of lipid antigens can inhibit NKT cell activation and NKT cell-mediated inflammation in NASH. These studies will provide novel insight into the mechanisms of metabolic control of immunity and shall contribute to the development of therapeutic strategies which target lipid antigen presentation at the origin of NKT cell-dependent inflammation in NASH.
肥胖症在世界范围内的发病率不断上升,并与炎症和恶性并发症有关。非酒精性脂肪性肝病(NAFLD)是一种常见的与肥胖相关的肝脏疾病,其特征是肝细胞脂质蓄积。虽然NAFLD通常显示良性病程,但肝脂肪变性可进展为称为非酒精性脂肪性肝炎(NASH)的炎症状态,这是肝纤维化和肝硬化的风险因素。主要参与这一过程的是自然杀伤T(NKT)细胞,这是一种在非典型MHC I类蛋白CD1d背景下识别脂质抗原的T细胞亚群。然而,虽然NKT细胞在NASH进展中的作用已被广泛表征,但参与NKT细胞活化的抗原的分子性质以及它们的细胞来源仍然未知。最近的研究表明,NAFLD从脂肪变性进展为脂肪性肝炎与肝脏溶血磷脂丰度增加有关。此外,我们可以证明肝细胞对溶血磷脂的CD 1d限制性呈递与肝NKT细胞的活化有关。因此,我们建议研究NAFLD中的代谢改变是否通过产生CD1d相关脂质抗原促进脂肪性肝炎中NKT细胞依赖性炎症。鉴于CD1d在肝抗原呈递细胞(APC)中广泛表达,我们建议首先使用条件性细胞特异性缺失CD1d的小鼠鉴定负责NASH中CD1d和NKT细胞介导的肝脏炎症的APC。第二,使用人类组织和小鼠工程表达表面可切割形式的CD1d,我们提出的特征,第一次,在体内与肝脏CD1d相关的脂质谱,并确定在CD1d相关的脂质,有助于NKT细胞依赖性NAFLD进展的库的变化。第三,我们建议研究靶向参与脂质抗原产生的代谢途径是否可以抑制NASH中NKT细胞活化和NKT细胞介导的炎症。这些研究将为免疫代谢控制机制提供新的见解,并将有助于开发针对NASH中NKT细胞依赖性炎症起源处的脂质抗原呈递的治疗策略。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin
  • DOI:
    10.1038/s41590-019-0504-0
  • 发表时间:
    2019-12-01
  • 期刊:
  • 影响因子:
    30.5
  • 作者:
    Melum, Espen;Jiang, Xiaojun;Blumberg, Richard S.
  • 通讯作者:
    Blumberg, Richard S.
Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells
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Professor Dr. Sebastian Zeissig其他文献

Professor Dr. Sebastian Zeissig的其他文献

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{{ truncateString('Professor Dr. Sebastian Zeissig', 18)}}的其他基金

Calcineurin-dependent effects of T cells in intestinal tumor development
T 细胞在肠道肿瘤发展中的钙调神经磷酸酶依赖性作用
  • 批准号:
    407400407
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
    Research Grants
X-linked inhibitor of apoptosis protein in intestinal homeostasis and the pathogenesis of inflammatory bowel disease
X连锁凋亡蛋白抑制剂在肠道稳态和炎症性肠病发病机制中的作用
  • 批准号:
    237611861
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Protektive und pathogene Rollen Natürlicher Killer T-Zellen in chronisch-entzündlichen Darmerkrankungen
自然杀伤 T 细胞在炎症性肠病中的保护和致病作用
  • 批准号:
    213893809
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Characterization of intestinal-epithelial calcineurin signaling in intestinal inflammation and tumor development
肠道炎症和肿瘤发展中肠上皮钙调神经磷酸酶信号传导的特征
  • 批准号:
    218581966
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Die Rolle des microsomalen Triglycerid-Transferproteins in Maus-Modellen chronisch entzündlicher Darmerkrankungen
微粒体甘油三酯转移蛋白在小鼠炎症性肠病模型中的作用
  • 批准号:
    28115764
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
    Research Fellowships
The role of SETDB1 in intestinal homeostasis and inflammation
SETDB1在肠道稳态和炎症中的作用
  • 批准号:
    445349847
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
STAT5 variants in the pathogenesis of inflammatory bowel disease
STAT5变异在炎症性肠病发病机制中的作用
  • 批准号:
    511537322
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
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Chemical proteomic investigation of lipid kinase specificity and druggability
脂质激酶特异性和成药性的化学蛋白质组学研究
  • 批准号:
    10660099
  • 财政年份:
    2023
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    --
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Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC
SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境
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    10657660
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Transendothelial transport and CD36 in the dysregulated lipid trafficking of failing hearts
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    2021
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Lipid Antigens for iNKT Cells in the Gut Microenvironment
肠道微环境中 iNKT 细胞的脂质抗原
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    10339377
  • 财政年份:
    2020
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Lipid Antigens for iNKT Cells in the Gut Microenvironment
肠道微环境中 iNKT 细胞的脂质抗原
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    10555286
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(PQ1) Lipid Metabolism, Inflammation, and T cell Dysfunction in HIV-associated Cancer
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    2017
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(PQ1) Lipid Metabolism, Inflammation, and T cell Dysfunction in HIV-associated Cancer
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Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension
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