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Lacy, Michael; Buerger, Christina; Shami, Annelie; Ahmadsei, Maiwand; Winkels, Holger; Nitz, Katrin; Tiel, Claudia M. van; Seijkens, Tom T. P.; Kusters, Pascal J. H.; Karshovka, Ela; Prange, Koen H. M.; Wu, Yuting; Brouns, Sanne L. N.; Unterlugauer, Sigrid; Kuijpers, Marijke J. E.; Reiche, Myrthe E.; Steffens, Sabine; Edsfeldt, Andreas; Megens, Remco T. A.; Heemskerk, Johan W. M.; Goncalves, Isabel; Weber, Christian; Gerdes, Norbert; Atzler, Dorothee and Lutgens, Esther (2021): Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease. In: Nature Communications, Vol. 12, No. 1, 3754

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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-gamma 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-gamma 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. Previous studies have shown that the CD40L-CD40 signaling axis plays a role in atherosclerosis. Here the authors investigate the cell-specific functions of the most relevant CD40L-expressing cell types in atherosclerosis. Deficiency of T cell-derived CD40L reduces and stabilizes plaques through impaired Th1 polarization while platelet-derived CD40L ameliorates atherothrombosis.

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