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Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

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2021

Nat Commun. 2021 Jun 18;12(1):3754. doi: 10.1038/s41467-021-23909-z.

Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

Michael Lacy, Christina Bürger, Annelie Shami, Maiwand Ahmadsei, Holger Winkel, Katrin Nitz, Claudia M van Tiel, Tom T P Seijkens, Pascal J H Kusters, Ela Karshovka, Koen H M Prange, Yuting Wu, Sanne L N Brouns, Sigrid Unterlugauer, Marijke J E Kuijpers, Myrthe E Reiche, Sabine Steffens, Andreas Edsfeldt, Remco T A Megens, Johan W M Heemskerk, Isabel Goncalves, Christian Weber, Norbert Gerdes, Dorothee Atzler, Esther Lutgens

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität, Munich, Germany. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. Department of Clinical Sciences Malmö, Lund University, Clinical Research Center, Malmö, Sweden. Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. Department III for Internal Medicine, University Hospital Cologne, Cologne, Germany. Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. Department of Cardiology, Skåne University Hospital, Lund University, Malmö, Sweden. Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität, Munich, Germany. Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität, Munich, Germany. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität, Munich, Germany. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität, Munich, Germany. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Service type: Knockout mice

Abstract

Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.

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