Lack of tolerogenic CD11c+ cells drives early atherosclerosis

M. Sauter (Mannheim)¹, F. Appenzeller (Tübingen)², K. Händler (Lübeck)³, H. Nording (Lübeck)⁴, R. J. Sauter (Mannheim)¹, C. A. Gleißner (Eggenfelden)⁵, S. Autenrieth (Heidelberg)⁶, D. Wolf (Freiburg im Breisgau)⁷, K. Stellos (Mannheim)⁸, D. Dürschmied (Mannheim)¹, T. Chavakis (Dresden)⁹, M. Nahrendorf (Boston)¹⁰, M. Spielmann (Lübeck)³, H. Langer (Mannheim)^1
1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; ²Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; 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.