Lack of tolerogenic CD11c+ cells drives early atherosclerosis [RNA-seq]
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- a, INF-? and IL-17. We furthermore detected a pronounced systemic inflammatory response with increased levels of TNF-a, INF?, IL-17 and IL-1ß. 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. Overall design: bulk 5' quantification mRNA-Seq of FACS-sorted mouse bone-marrow-derived CD11c positive cells. 4 replicates each of cells incubated for 24h with acLDL (to mimic an atherosclerotic environment) vs control.