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Constitutive CD40 Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption.

Authors
  • Kusters, Pascal1
  • Seijkens, Tom1
  • Bürger, Christina2
  • Legein, Bart3
  • Winkels, Holger2
  • Gijbels, Marion4
  • Barthels, Christian5
  • Bennett, Remy1
  • Beckers, Linda1
  • Atzler, Dorothee6
  • Biessen, Erik7
  • Brocker, Thomas5
  • Weber, Christian2
  • Gerdes, Norbert8
  • Lutgens, Esther9
  • 1 Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. , (Netherlands)
  • 2 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilian University of Munich, Munich, Germany. , (Germany)
  • 3 Department of Pathology, Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands. , (Netherlands)
  • 4 Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Pathology, Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands. , (Netherlands)
  • 5 Institute for Immunology, Ludwig-Maximilian University of Munich, Munich, Germany. , (Germany)
  • 6 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilian University of Munich, Munich, Germany; Walther-Straub-Institut for Pharmacology and Toxicology, Ludwig Maximilians University, Munich, Germany. , (Germany)
  • 7 Department of Pathology, Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), Klinikum RWTH Aachen, Aachen, Germany. , (Germany)
  • 8 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilian University of Munich, Munich, Germany; Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany. , (Germany)
  • 9 Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilian University of Munich, Munich, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Dec 01, 2017
Volume
187
Issue
12
Pages
2912–2919
Identifiers
DOI: 10.1016/j.ajpath.2017.08.016
PMID: 28935569
Source
Medline
License
Unknown

Abstract

The costimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types, including mature dendritic cells (DCs), and is required for optimal T-cell activation and expansion. It remains undetermined whether and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here, the effects of constitutively active CD40 in DCs on atherosclerosis were examined using low-density lipoprotein-deficient (Ldlr-/-) bone marrow chimeras that express a transgene containing an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the DC-specific CD11c promoter (DC-LMP1/CD40). As expected, DC-LMP1/CD40/Ldlr-/- chimeras (DC-LMP1/CD40) showed increased antigen-presenting capacity of DCs and increased T-cell numbers. However, the mice developed extensive neutrophilia compared to CD40wt/Ldlr-/- (CD40wt) chimeras. Despite overt T-cell expansion and neutrophilia, a reduction in conventional DC frequency and a dramatic (approximately 80%) reduction in atherosclerosis was observed. Further analyses revealed that cholesterol and triglyceride levels had decreased by 37% and 60%, respectively, in DC-LMP1/CD40 chimeras. Moreover, DC-LMP1/CD40 chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.

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