CD11c.DTR mice develop a fatal fulminant myocarditis after local or systemic treatment with diphtheria toxin |
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| Authors: | Linda Männ Nora Kochupurakkal Christian Martin Eva Verjans Anika Klingberg Simon Sody Andreas Kraus Jill Dalimot Eileen Bergmüller Steffen Jung Sylvia Voortman Elke Winterhager Sven Brandau Natalio Garbi Michael Kurrer Urs Eriksson Mike Hasenberg |
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| Affiliation: | 1. Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg–Essen, Essen, Germany;2. Department of Research, Experimental Critical Care Medicine, University Hospital, Basel, Switzerland;3. Institute of Pharmacology and Toxicology, University Hospital Aachen, Aachen, Germany;4. Institute of Pediatrics, University Hospital Aachen, Aachen, Germany;5. Department of Otorhinolaryngology, University Hospital, University Duisburg–Essen, Essen, Germany;6. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel;7. Imaging Center Essen, Electron Microscopy Unit, University Hospital, University Duisburg–Essen, Essen, Germany;8. Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;9. Gemeinschaftspraxis für Pathologie, Zurich, Switzerland;10. Division of Cardioimmunology, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland;11. Department of Medicine, GZO—Zurich Regional Health Center, Wetzikon, Switzerland;12. Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg–Essen, Essen, GermanyThese authors are coprincipal investigators of this work. |
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| Abstract: | To assess the role of alveolar macrophages (AMs) during a pulmonary Aspergillus fumigatus infection AMs were depleted by intratracheal application of diphtheria toxin (DTX) to transgenic CD11c.DTR mice prior to fungal infection. Unexpectedly, all CD11c.DTR mice treated with DTX died within 4–5 days, whether being infected with A. fumigatus or not. Despite measurable impact of DTX on lung functional parameters, these constrictions could not explain the high mortality rate. Instead, DTX‐treated CD11c.DTR animals developed fulminant myocarditis (FM) characterized by massive leukocyte infiltration and myocardial cell destruction, including central parts of the heart's stimulus transmission system. In fact, standard limb lead ECG recordings of diseased but not healthy mice showed a “Brugada”‐like pattern with an abnormally high ST segment pointing to enhanced susceptibility for potential lethal arrhythmias. While CD11c.DTR mice are extensively used for the characterization of CD11c+ cells, including dendritic cells, several studies have already mentioned adverse side effects following DTX treatment. Our results demonstrate that this limitation is based on severe myocarditis but not on the expected lung constrictions, and has to be taken into consideration if this animal model is used. Based on these properties, however, the CD11c.DTR mouse might serve as useful animal model for FM. |
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| Keywords: | CD11c.DTR ⋅ Conditional knockout ⋅ Diphtheria toxin ⋅ Infection ⋅ Myocarditis ⋅ Transgenic mice |
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