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

Michael Lacy, Christina Bürger, Annelie Shami, Maiwand Ahmadsei, Holger Winkels, Katrin Nitz, Claudia M. 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. Heemskerk, Isabel Goncalves, Christian Weber, Norbert Gerdes (), Dorothee Atzler () and Esther Lutgens ()
Additional contact information
Michael Lacy: Ludwig-Maximilians-Universität
Christina Bürger: Ludwig-Maximilians-Universität
Annelie Shami: Lund University, Clinical Research Center
Maiwand Ahmadsei: Ludwig-Maximilians-Universität
Holger Winkels: Ludwig-Maximilians-Universität
Katrin Nitz: Ludwig-Maximilians-Universität
Claudia M. Tiel: University of Amsterdam
Tom T. P. Seijkens: University of Amsterdam
Pascal J. H. Kusters: University of Amsterdam
Ela Karshovka: Ludwig-Maximilians-Universität
Koen H. M. Prange: University of Amsterdam
Yuting Wu: Ludwig-Maximilians-Universität
Sanne L. N. Brouns: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University
Sigrid Unterlugauer: Ludwig-Maximilians-Universität
Marijke J. E. Kuijpers: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University
Myrthe E. Reiche: University of Amsterdam
Sabine Steffens: Ludwig-Maximilians-Universität
Andreas Edsfeldt: Lund University, Clinical Research Center
Remco T. A. Megens: Ludwig-Maximilians-Universität
Johan W. M. Heemskerk: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University
Isabel Goncalves: Lund University, Clinical Research Center
Christian Weber: Ludwig-Maximilians-Universität
Norbert Gerdes: Ludwig-Maximilians-Universität
Dorothee Atzler: Ludwig-Maximilians-Universität
Esther Lutgens: Ludwig-Maximilians-Universität

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23909-z

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