https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2LKH-Univ. Klinikum Graz - Universitätsklinik für Innere Medizin Experimentelle Kardiologie Graz, Österreich; 3Universitätsklinikum Schleswig-Holstein Lübeck, Deutschland; 4Universitätsklinikum Schleswig-Holstein Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin Lübeck, Deutschland; 5Rottal-Inn-Kliniken Eggenfelden Innere Medizin II - Kardiologie, Schlaganfallzentrum Eggenfelden, Deutschland; 6Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Deutschland; 7Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland; 8Universitätsmedizin Mannheim der Universität Heidelberg Institut für Herz-Kreislaufforschung Mannheim, Deutschland; 9Universitätsklinikum Carl Gustav Carus an der TU Dresden Institut für klinische Chemie und Laboratoriumsmedizin Dresden, Deutschland; 10Center for Systems Biology Harvard Medical School Boston, USA
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.