Lack of tolerogenic CD11c+ cells drives early atherosclerosis [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1152993 | ENA |
REPOSITORIES: ENA
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Project description:Lack of tolerogenic CD11c+ cells drives early atherosclerosis [scRNA-seq]
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Project description:Atherosclerosis is a chronic disease characterized by both dysregulated lipid metabolism and a sustained inflammatory reaction. To study exuberant inflammation as the main trigger of atherosclerosis, we established a novel in vivo approach to induce predominantly “immune-triggered atherosclerosis” for early atherogenesis independent of lipid dysregulation. Bone marrow from CD11c.DTR-GFP mice, which express the receptor for diphtheria toxin (DT) under control of the CD11c promoter, was transplanted into female C57BL/6 mice, and long-term depletion of antigen-presenting CD11c+ cells following DT administration was achieved without affecting lipid homeostasis. These mice exhibited enhanced atherosclerosis (~300%) in comparison to mice without CD11c+ cell depletion. Interestingly, we observed an altered immune cell composition within the aortic wall, including a decrease in tolerogenic DCs, a shift towards inflammatory Ly6G+/Ly6C+ monocytes and increased CD25+/FoxP3+ T cells, whereby the intracellular cytokine profile showed an increase of TNF- α, INF-γ and IL-17. We furthermore detected a pronounced systemic inflammatory response with increased levels of TNF-α, INFγ, IL-17 and IL-1β. Thus, CD11c+ cells are the decisive cellular brake preventing an exuberant inflammatory response in early atherogenesis. Here, we describe a novel tool for studying the role of immune cells and associated mechanisms in atherosclerosis in mice with intact lipid metabolism.
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Project description:Atherosclerosis is a chronic disease characterized by both dysregulated lipid metabolism and a sustained inflammatory reaction. To study exuberant inflammation as the main trigger of atherosclerosis, we established a novel in vivo approach to induce predominantly “immune-triggered atherosclerosis” for early atherogenesis independent of lipid dysregulation. Bone marrow from CD11c.DTR-GFP mice, which express the receptor for diphtheria toxin (DT) under control of the CD11c promoter, was transplanted into female C57BL/6 mice, and long-term depletion of antigen-presenting CD11c+ cells following DT administration was achieved without affecting lipid homeostasis. These mice exhibited enhanced atherosclerosis (~300%) in comparison to mice without CD11c+ cell depletion. Interestingly, we observed an altered immune cell composition within the aortic wall, including a decrease in tolerogenic DCs, a shift towards inflammatory Ly6G+/Ly6C+ monocytes and increased CD25+/FoxP3+ T cells, whereby the intracellular cytokine profile showed an increase of TNF- α, INF-γ and IL-17. We furthermore detected a pronounced systemic inflammatory response with increased levels of TNF-α, INFγ, IL-17 and IL-1β. Thus, CD11c+ cells are the decisive cellular brake preventing an exuberant inflammatory response in early atherogenesis. Here, we describe a novel tool for studying the role of immune cells and associated mechanisms in atherosclerosis in mice with intact lipid metabolism.
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Project description:JAG1-NOTCH4 mechanosensing drives atherosclerosis
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Project description:Endothelial cell (EC) sensing of fluid shear stress regulates atherosclerosis, a disease of arteries that causes heart attack and stroke. Atherosclerosis preferentially develops at regions of arteries exposed to low oscillatory shear stress (LOSS), whereas high shear regions are protected. We show using inducible EC-specific genetic deletion in hyperlipidaemic mice that the Notch ligands JAG1 and DLL4 have opposing roles in atherosclerosis. While endothelial Jag1 promoted atherosclerosis at sites of LOSS, endothelial Dll4 was atheroprotective. Analysis of porcine and murine arteries and cultured human coronary artery EC exposed to experimental flow revealed that JAG1 and its receptor NOTCH4 are strongly upregulated by LOSS. Functional studies in cultured cells and in mice with EC-specific deletion of Jag1 show that JAG1-NOTCH4 signalling drives vascular dysfunction by repressing endothelial repair. These data demonstrate a fundamental role for JAG1-NOTCH4 in sensing LOSS during disease, and suggest therapeutic targeting of this pathway to treat atherosclerosis.
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