Role of orphan receptor GPR55 in immune cell homeostasis and atherosclerosis

点击翻译按钮获取中文摘要

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.