In situ lipid-loading activates peripheral dendritic cell subsets characterized by cellular ROS accumulation but compromises their capacity to prime naïve T cells
Free Radical Biology and Medicine, vol. 210, pp. 406–415
Abstract
Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established. In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr−/−) mice on separate DC subsets, their compartmentalization and functionality. While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4+ T cells. Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.
Authors 13
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Anette Christ corresponding
Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Health Office Frankfurt/Main, Frankfurt/Main, Germany. Electronic address: anette.christ@stadt-frankfurt.de
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
Health Office Frankfurt/Main, Frankfurt/Main, Germany
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Sanne Lidewij Maas Aachen Institute for Molecular Cardiovascular Research (IMCAR) Interdisciplinary Center for Clinical Research (IZKF)
Affiliation as printed
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
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Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
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Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
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Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
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Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
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Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
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Maastricht University Medical Centre
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
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Affiliation as printed
Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
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Martin Zenke Aachen Institute for Biomedical Engineering Department of Cell Biology Department of Hematology, Oncology and Stem Cell Transplantation
Affiliation as printed
Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, 52074, Aachen, Germany; Department of Hematology, Oncology and Stem Cell Transplantation, RWTH Aachen University Medical School, 52074, Aachen, Germany
Department of Hematology, Oncology and Stem Cell Transplantation, RWTH Aachen University Medical School, 52074, Aachen, Germany
Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, 52074, Aachen, Germany
Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
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University of Münster · Maastricht University Medical Centre
Affiliation as printed
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms-University, Münster, Germany
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms-University, Münster, Germany
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Maastricht University Medical Centre · RWTH Aachen University
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
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Emiel P. C. van der Vorst corresponding Aachen Institute for Molecular Cardiovascular Research (IMCAR) Interdisciplinary Center for Clinical Research (IZKF)
Maastricht University Medical Centre · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten · Ludwig-Maximilians-Universität München · RWTH Aachen University
Affiliation as printed
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: evandervorst@ukaachen.de
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
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