Unveiling Immune Dynamics in Atherosclerosis: Insights from a bone marrow chimeric murine model

Clin Res Cardiol (2024). DOI 10.1007/s00392-024-02526-y
M. Sauter (Mannheim)¹, F. Appenzeller (Graz)², K. Händler (Lübeck)³, Z. Aherrahrou (Lübeck)³, F. Emschermann (Tübingen)⁴, M. Olbrich (Tübingen)⁴, H. Nording (Lübeck)⁵, H. Emami (Lübeck)⁵, R. J. Sauter (Mannheim)⁶, C. A. Gleißner (Eggenfelden)⁷, S. Autenrieth (Heidelberg)⁸, D. Wolf (Freiburg im Breisgau)⁹, D. Dürschmied (Mannheim)⁶, T. Chavakis (Dresden)¹⁰, K. Stellos (Mannheim)¹, N. Nahrendorf (Boston)¹¹, M. Spielmann (Lübeck)³, H. Langer (Mannheim)^6
1Universitätsmedizin Mannheim der Universität Heidelberg Institut für Herz-Kreislaufforschung Mannheim, Deutschland; ²LKH-Univ. Klinikum Graz - Universitätsklinik für Innere Medizin Klinische Abteilung für Kardiologie Graz, Österreich; ³Universitätsklinikum Schleswig-Holstein Lübeck, Deutschland; ⁴Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; ⁵Universitätsklinikum Schleswig-Holstein Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin Lübeck, Deutschland; ⁶Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; ⁷Rottal-Inn-Kliniken Eggenfelden Innere Medizin II - Kardiologie, Schlaganfallzentrum Eggenfelden, Deutschland; ⁸Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Deutschland; ⁹Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland; ¹⁰Universitätsklinikum Carl Gustav Carus an der TU Dresden Institut für klinische Chemie und Laboratoriumsmedizin Dresden, Deutschland; ¹¹Center for Systems Biology Harvard Medical School Boston, USA

Atherosclerosis is a chronic disease characterized by both dysregulated lipid metabolism and a sustained inflammatory reaction. To study atherosclerosis, genetic mouse models that include mutations in central components of lipid metabolism and thus, mimic symptoms of atherosclerosis, are traditionally utilized. Models of atherosclerosis based predominantly on inflammation-driven mechanisms are, however, unavailable. Thus, to date, it has been impossible to precisely define changes in the immune cell compartment during atherogenesis independent of disturbed lipid homeostasis.

We established a novel in vivo approach to induce predominantly “immune-triggered atherosclerosis” by employing transgenic CD11c+.DTR mice, which express the receptor for diphtheria toxin (DT) under control of the CD11c promoter. Bone marrow from CD11c.DTR-GFP mice was transplanted into wild-type C57BL/6 mice, generating a bone marrow chimeric mouse model in which long-term depletion of antigen-presenting CD11c+ cells following DT administration was achieved, bypassing the need to target molecules involved in lipid homeostasis. These mice exhibited enhanced atherosclerotic plaque formation in comparison to undepleted control mice. In the model mice, we observed an altered immune cell composition within the aortic wall, including a decrease in tolerogenic DCs; a shift toward inflammatory Ly6G+/Ly6C+ monocytes; and changes in the T cell populations. This change in the immune cell compartment was accompanied by an increased systemic inflammatory response in lymphatic organs and blood circulation, with increased levels of TNF-α, INFγ, IL-17 and IL-1β.

With this model, we provide a novel tool for studying the role of immune cells and associated mechanisms in atherosclerosis in mice with intact lipid metabolism, which will help to further characterize the role of inflammation in atherosclerosis and may be adapted to study the roles of specific cell types in other diseases.