TY - JOUR
T1 - Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease
AU - Lacy, Michael
AU - Bürger, Christina
AU - Shami, Annelie
AU - Ahmadsei, Maiwand
AU - Winkels, Holger
AU - Nitz, Katrin
AU - van Tiel, Claudia M.
AU - Seijkens, Tom T. P.
AU - Kusters, Pascal J. H.
AU - Karshovka, Ela
AU - Prange, Koen H. M.
AU - Wu, Yuting
AU - Brouns, Sanne L. N.
AU - Unterlugauer, Sigrid
AU - Kuijpers, Marijke J. E.
AU - Reiche, Myrthe E.
AU - Steffens, Sabine
AU - Edsfeldt, Andreas
AU - Megens, Remco T. A.
AU - Heemskerk, Johan W. M.
AU - Goncalves, Isabel
AU - Weber, Christian
AU - Gerdes, Norbert
AU - Atzler, Dorothee
AU - Lutgens, Esther
N1 - 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 Skåne are acknowledged for generous financial support. Graphics for Fig. 5a and b were created with BioRender.com. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108166990&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-23909-z
DO - https://doi.org/10.1038/s41467-021-23909-z
M3 - Article
C2 - 34145241
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3754
ER -