@article{5ddefbaf56f3478eb7b4cbd26e415728,
title = "Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease",
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.",
keywords = "REGULATORY T-CELLS, SOLUBLE CD40 LIGAND, THROMBUS FORMATION, GENE-EXPRESSION, MICE, IMMUNITY, ANTIBODY, GROWTH, INFLAMMATION, INHIBITION",
author = "Michael Lacy and Christina Buerger and Annelie Shami and Maiwand Ahmadsei and Holger Winkels and Katrin Nitz and {van Tiel}, {Claudia M.} and Seijkens, {Tom T. P.} and Kusters, {Pascal J. H.} and Ela Karshovka and Prange, {Koen H. M.} and Yuting Wu and Brouns, {Sanne L. N.} and Sigrid Unterlugauer and Kuijpers, {Marijke J. E.} and Reiche, {Myrthe E.} and Sabine Steffens and Andreas Edsfeldt and Megens, {Remco T. A.} and Heemskerk, {Johan W. M.} and Isabel Goncalves and Christian Weber and Norbert Gerdes and Dorothee Atzler and Esther Lutgens",
note = "Funding Information: This study was supported by the Deutsche Forschungsgemeinschaft [CRC 1123 to D.A., E.L., N.G., S.S., R.M., C.W., TRR259 to N.G & E.L]. We also acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” [CVON2017-20]. This study was also supported by the Netherlands Organization for Scientific Research (NWO) [VICI grant to E.L.]; the EU (Horizon 2020, REPROGRAM to E.L.); the German Centre for Cardiovascular Research (DZHK) [High-risk high-volume (HRHV) grant to E.L, D.A. and C.W.] and the European Research Council [ERC consolidator grant to E.L, ERC advanced grant to C.W.]. C.W. is a Van de Laar professor of atherosclerosis. Further support was received from the Swedish Research Council (A.E, I.G), Swedish Heart and Lung Foundation (A.S, A.E, I.G), Swedish Society for Medical Research (A.E), Swedish Heart and Lung Association (A.S), Swedish Stroke Association (A.S.) and the Swedish Foundation for Strategic Research Dnr IRC15-0067. The Knut and Alice Wallenberg foundation, the Medical Faculty at Lund University and Region Sk{\aa}ne are acknowledged for generous financial support. Graphics for Fig. 5a and b were created with BioRender.com. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = jun,
day = "18",
doi = "10.1038/s41467-021-23909-z",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}