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

• Published in: Nature communications Vol. 12; no. 1; p. 3754
• Main 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., Goncalves, Isabel, Weber, Christian, Gerdes, Norbert, Atzler, Dorothee, Lutgens, Esther
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-06-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/21; 13/31; 13/51; 631/250/256; 64; 64/110; 692/4019/592/1339; 692/4019/592/75/593/2100; Animals; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - pathology; Basic Medicine; Blood Platelets - metabolism; Cardiovascular diseases; Cardiovascular Diseases - pathology; CD11c antigen; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; CD40 antigen; CD40 Antigens - metabolism; CD40 Ligand - metabolism; CD40L protein; Cell interactions; Cerebrovascular diseases; Dendritic cells; Dendritic Cells - immunology; Humanities and Social Sciences; Immunologi inom det medicinska området; Immunology in the medical area; Interferon; Interferon-gamma - metabolism; Lymphocytes; Lymphocytes T; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Knockout; multidisciplinary; Muscles; Myocytes, Smooth Muscle - cytology; Plaque, Atherosclerotic - pathology; Plaques; Platelets; Polarization; Science; Science (multidisciplinary); Signal Transduction - physiology; Signaling; Smooth muscle; Thrombosis - pathology; Vascular diseases; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23909-z

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.