Atherosclerosis is characterized by both dysregulated lipid metabolism and chronic inflammation. 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 diphtheria toxin receptor under control of the CD11c promoter, was transplanted into C57BL/6 mice, and long-term depletion of antigen-presenting CD11c+ cells following diphtheria toxin administration was achieved without affecting lipid homeostasis. Surprisingly, these mice exhibited severely accelerated atherosclerosis under high cholesterol diet 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. Within the T cell population, we found an elevated expression of TNF-α, IFN-γ, and IL-17. We furthermore detected a pronounced systemic inflammatory response with increased levels of TNF-α, INFγ, IL-17 and IL-1β in blood.
Thus, CD11c+ cells are the decisive cellular brake preventing an exuberant inflammatory response in early atherogenesis. We describe a novel tool for studying the role of immune cells and associated mechanisms in atherosclerosis in mice with unchanged lipid parameters.
