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

Michael Lacy, Christina Bürger, Annelie Shami, Maiwand Ahmadsei, Holger Winkels, 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. HeemskerkIsabel Goncalves, Christian Weber, Norbert Gerdes, Dorothee Atzler, Esther Lutgens

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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.
Original languageEnglish
Article number3754
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2021

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