Role of orphan receptor GPR55 in immune cell homeostasis and atherosclerosis

孤儿受体GPR55在免疫细胞稳态和动脉粥样硬化中的作用

• 批准号: 406945731
• 负责人: Professorin Dr. Sabine Steffens
• 金额: --
• 依托单位: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/406945731?language=en
• 关键词: Role; orphan; receptor; GPR55; immune

Acute cardiovascular complications related to atherosclerosis are the leading cause of death worldwide. It is increasingly considered that the underlying chronic inflammatory process, which promotes arterial plaque formation and progression, could be a therapeutic target to limit the risk of acute cardiovascular events such as myocardial infarction. In this context, we are interested in the role of the endocannabinoid system, an endogenous lipid signaling system, in chronic inflammatory responses contributing to atherosclerosis. The orphan receptor GPR55 has been proposed as a novel cannabinoid receptor, based on high affinity binding to synthetic and endogenous cannabinoids. Later, it was identified that lysophosphatidylinositol (LPI) is a more potent endogenous ligand. According to murine microarray databases, GPR55 is expressed by various lymphocyte subsets, in particular gammadeltaT (gdT) cells. Its role in regulating immune functions in the context of atherosclerosis is unknown.To dissect its role in atherosclerosis, we crossed apolipoprotein E deficient (Apoe-/- ) mice with GPR55-/- mice to generate Apoe-/-GPR55-/- mice. Our preliminary experiments revealed approximately two-fold larger plaque sizes in Apoe-/-GPR55-/- mice compared to ApoE-/- controls with higher plaque macrophage content at early stage, but less macrophage and more collagen content at advanced atherosclerosis. This was accompanied by enhanced aortic pro-inflammatory cytokine mRNA expression and upregulated IgG1 plasma levels. Moreover, GPR55 deficiency was associated with increased lymphocyte counts, with the most striking increase found in gdT cells. Based on our preliminary findings, the aim of this project is to clarify the role of GPR55 signaling in immune cell homeostatic function, and how this modulates atherosclerotic plaque development. Our working hypothesis is that GPR55 signaling negatively regulates gdT cell activation and cytotoxic lymphocyte responses. We may speculate that LPI, the natural ligand for GPR55, is a homeostatic retention signal for gdT cells in lymphoid tissues. In particular, we want to address four specific questions: (1) Which immune cell subsets express GPR55? Do GPR55 expression levels change in atherosclerosis? (2) Which tissues highly express the natural ligand LPI? Are LPI tissue levels modulated in atherosclerosis? (3) What is the specific contribution of hematopoietic GPR55 deficiency in atherosclerosis and metabolic changes (weight and cholesterol levels)? (4) How does GPR55 negatively control gdT cell activation?We believe that this project is highly relevant, as the specific role of lymphocyte GPR55 signaling in atherosclerosis is unknown.

与动脉粥样硬化相关的急性心血管并发症是全球主要的死亡原因。越来越多的人认为，促进动脉斑块形成和进展的潜在慢性炎症过程可能成为限制急性心血管事件(如心肌梗死)风险的治疗靶点。在这种背景下，我们感兴趣的是内源性脂质信号系统--内源性大麻素系统在导致动脉粥样硬化的慢性炎症反应中的作用。孤儿受体GPR55被认为是一种新的大麻素受体，它与合成的和内源性的大麻素具有高亲和力。后来，人们发现溶血磷脂酰肌醇(LPI)是一种更有效的内源性配体。根据小鼠基因芯片数据库，GPR55由各种淋巴细胞亚群表达，尤其是GDT细胞。它在动脉粥样硬化背景下调节免疫功能的作用尚不清楚。为了剖析它在动脉粥样硬化中的作用，我们将载脂蛋白E缺陷(APOE-/-)小鼠与GPR55-/-小鼠杂交，产生了APOE-/-GPR55-/-小鼠。我们的初步实验显示，APOE-/-GPR55-/-小鼠的斑块大小大约是ApoE-/-对照组的两倍，早期斑块中巨噬细胞含量较高，但在动脉粥样硬化晚期，巨噬细胞较少，胶原含量较多。伴随而来的是主动脉促炎症细胞因子基因表达的增强和血浆中IgG1水平的升高。此外，GPR55缺乏与淋巴细胞计数增加有关，其中以GDT细胞的增加最为显著。基于我们的初步发现，本项目的目的是阐明GPR55信号在免疫细胞稳态功能中的作用，以及这如何调节动脉粥样硬化斑块的发展。我们的工作假设是GPR55信号负性调节GDT细胞激活和细胞毒性淋巴细胞反应。我们可能推测LPI是GPR55的天然配体，是淋巴组织中GDT细胞的动态平衡保持信号。特别是，我们想要解决四个具体的问题：(1)哪些免疫细胞亚群表达GPR55？GPR55在动脉粥样硬化中的表达水平是否改变？(2)哪些组织高表达天然配体LPI？LPI组织水平在动脉粥样硬化中是否受到调节？(3)GPR55缺乏对动脉粥样硬化和代谢变化(体重和胆固醇水平)的具体贡献是什么？(4)GPR55如何负向控制GDT细胞的激活？我们认为这个项目非常相关，因为淋巴细胞GPR55信号在动脉粥样硬化中的具体作用尚不清楚。