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

Lacy, Michael ; Bürger, Christina ; Shami, Annelie LU orcid ; Ahmadsei, Maiwand ; Winkels, Holger ; Nitz, Katrin ; van Tiel, Claudia M. ; Seijkens, Tom T.P. ; Kusters, Pascal J.H. and Karshovka, Ela , et al. (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.

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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
2024-06-16 16:38:22
@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}},
}