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

Michael Lacy, Christina Buerger, 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)

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-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.

Original languageEnglish
Article number3754
Number of pages12
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 18 Jun 2021

Keywords

  • REGULATORY T-CELLS
  • SOLUBLE CD40 LIGAND
  • THROMBUS FORMATION
  • GENE-EXPRESSION
  • MICE
  • IMMUNITY
  • ANTIBODY
  • GROWTH
  • INFLAMMATION
  • INHIBITION

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