Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease
(2021) In Nature Communications 12(1).- 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.... (More)
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.
(Less)
- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 12
- issue
- 1
- article number
- 3754
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85108166990
- pmid:34145241
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-021-23909-z
- language
- English
- LU publication?
- yes
- id
- b3e13e99-f103-44b7-94b5-eb8ee468942e
- date added to LUP
- 2021-08-11 09:06:29
- date last changed
- 2024-09-21 23:02:28
@article{b3e13e99-f103-44b7-94b5-eb8ee468942e, abstract = {{<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>}}, author = {{Lacy, Michael and Bürger, Christina and Shami, Annelie and Ahmadsei, Maiwand and Winkels, Holger and Nitz, Katrin and van Tiel, Claudia M. and Seijkens, Tom T.P. and Kusters, Pascal J.H. and Karshovka, Ela and Prange, Koen H.M. and Wu, Yuting and Brouns, Sanne L.N. and Unterlugauer, Sigrid and Kuijpers, Marijke J.E. and Reiche, Myrthe E. and Steffens, Sabine and Edsfeldt, Andreas and Megens, Remco T.A. and Heemskerk, Johan W.M. and Goncalves, Isabel and Weber, Christian and Gerdes, Norbert and Atzler, Dorothee and Lutgens, Esther}}, issn = {{2041-1723}}, language = {{eng}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease}}, url = {{http://dx.doi.org/10.1038/s41467-021-23909-z}}, doi = {{10.1038/s41467-021-23909-z}}, volume = {{12}}, year = {{2021}}, }