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- Title
Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease.
- Authors
Lacy, Michael; Bürger, Christina; Shami, Annelie; Ahmadsei, Maiwand; Winkels, Holger; Nitz, Katrin; van Tiel, Claudia M.; 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.
- 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. 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.
- Subjects
VASCULAR diseases; CARDIOVASCULAR diseases; ATHEROSCLEROTIC plaque; ATHEROSCLEROSIS; MUSCLE cells
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-23909-z