Lacy, Michael ORCID: 0000-0001-5944-582X, Buerger, Christina, Shami, Annelie, Ahmadsei, Maiwand ORCID: 0000-0002-0646-2762, 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 ORCID: 0000-0002-2935-0181, Weber, Christian ORCID: 0000-0003-4610-8714, Gerdes, Norbert, Atzler, Dorothee and Lutgens, Esther (2021). Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease. Nat. Commun., 12 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lacy, MichaelUNSPECIFIEDorcid.org/0000-0001-5944-582XUNSPECIFIED
Buerger, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shami, AnnelieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmadsei, MaiwandUNSPECIFIEDorcid.org/0000-0002-0646-2762UNSPECIFIED
Winkels, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nitz, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Tiel, Claudia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seijkens, Tom T. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kusters, Pascal J. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karshovka, ElaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prange, Koen H. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, YutingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brouns, Sanne L. N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unterlugauer, SigridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuijpers, Marijke J. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiche, Myrthe E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steffens, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edsfeldt, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Megens, Remco T. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heemskerk, Johan W. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goncalves, IsabelUNSPECIFIEDorcid.org/0000-0002-2935-0181UNSPECIFIED
Weber, ChristianUNSPECIFIEDorcid.org/0000-0003-4610-8714UNSPECIFIED
Gerdes, NorbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Atzler, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lutgens, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-600308
DOI: 10.1038/s41467-021-23909-z
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
REGULATORY T-CELLS; SOLUBLE CD40 LIGAND; THROMBUS FORMATION; GENE-EXPRESSION; MICE; IMMUNITY; ANTIBODY; GROWTH; INFLAMMATION; INHIBITIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60030

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