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June 30, 2023 article Open access Aachen paper

Single-cell profiling reveals age-associated immunity in atherosclerosis

Cardiovascular Research, vol. 119, pp. 2508–2521

DOI: 10.1093/cvr/cvad099 Full text (OA) OpenAlex

Abstract

AIMS: Aging is a dominant driver of atherosclerosis and induces a series of immunological alterations, called immunosenescence. Given the demographic shift towards elderly, elucidating the unknown impact of aging on the immunological landscape in atherosclerosis is highly relevant. While the young Western diet-fed Ldlr-deficient (Ldlr-/-) mouse is a widely used model to study atherosclerosis, it does not reflect the gradual plaque progression in the context of an aging immune system as occurs in humans. METHODS AND RESULTS: Here, we show that aging promotes advanced atherosclerosis in chow diet-fed Ldlr-/- mice, with increased incidence of calcification and cholesterol crystals. We observed systemic immunosenescence, including myeloid skewing and T-cells with more extreme effector phenotypes. Using a combination of single-cell RNA-sequencing and flow cytometry on aortic leucocytes of young vs. aged Ldlr-/- mice, we show age-related shifts in expression of genes involved in atherogenic processes, such as cellular activation and cytokine production. We identified age-associated cells with pro-inflammatory features, including GzmK+CD8+ T-cells and previously in atherosclerosis undefined CD11b+CD11c+T-bet+ age-associated B-cells (ABCs). ABCs of Ldlr-/- mice showed high expression of genes involved in plasma cell differentiation, co-stimulation, and antigen presentation. In vitro studies supported that ABCs are highly potent antigen-presenting cells. In cardiovascular disease patients, we confirmed the presence of these age-associated T- and B-cells in atherosclerotic plaques and blood. CONCLUSIONS: Collectively, we are the first to provide comprehensive profiling of aged immunity in atherosclerotic mice and reveal the emergence of age-associated T- and B-cells in the atherosclerotic aorta. Further research into age-associated immunity may contribute to novel diagnostic and therapeutic tools to combat cardiovascular disease.

Authors 25

  1. Virginia Smit Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  2. Jill de Mol Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  3. Frank H. Schaftenaar Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  4. Marie A.C. Depuydt Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  5. Rimke J. Postel Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  6. Diede Smeets Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  7. F.W. Verheijen Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  8. Laurens Bogers Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  9. Janine van Duijn Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  10. Robin A.F. Verwilligen Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  11. Hendrika W. Grievink Aachen Centre for Human Drug Research (CHDR) Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University · Centre for Human Drug Research

    Affiliation as printed

    Centre for Human Drug Research , Zernikedreef 8, 2333 CL Leiden , The Netherlands

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  12. Mireia N. A. Bernabé Kleijn Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  13. Eva van Ingen Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  14. Maaike J.M. de Jong Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  15. Lauren N. Goncalves

    Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum

    Affiliation as printed

    Department of Surgery, Haaglanden Medical Center—location Westeinde , Lijnbaan 32, 2515 VA The Hague , The Netherlands

  16. Judith A. H. M. Peeters

    Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum

    Affiliation as printed

    Department of Surgery, Haaglanden Medical Center—location Westeinde , Lijnbaan 32, 2515 VA The Hague , The Netherlands

  17. Harm J. Smeets

    Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum

    Affiliation as printed

    Department of Surgery, Haaglanden Medical Center—location Westeinde , Lijnbaan 32, 2515 VA The Hague , The Netherlands

  18. Anouk Wezel

    Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum

    Affiliation as printed

    Department of Surgery, Haaglanden Medical Center—location Westeinde , Lijnbaan 32, 2515 VA The Hague , The Netherlands

  19. Julia K. Polansky

    Berlin-Brandenburger Centrum für Regenerative Therapien · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Berlin Institute of Health at Charité—Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT) , Augustenburger Platz 1, 13353 Berlin , Germany

  20. Menno P.J. de Winther

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam

    Affiliation as printed

    Amsterdam University Medical Centers—location AMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences , Meibergdreef 9, 1105 AZ Amsterdam , The Netherlands

  21. Christoph J. Binder

    Vienna General Hospital · Medical University of Vienna

    Affiliation as printed

    Department of Laboratory Medicine, Medical University of Vienna , Lazarettgasse 14, AKH BT25.2, 1090 Vienna , Austria

  22. Dimitrios Tsiantoulas

    Vienna General Hospital · Medical University of Vienna

    Affiliation as printed

    Department of Laboratory Medicine, Medical University of Vienna , Lazarettgasse 14, AKH BT25.2, 1090 Vienna , Austria

  23. Ilze Bot Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  24. Johan Kuiper Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

  25. Amanda C. Foks corresponding Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research, Division of BioTherapeutics, Leiden University , Einsteinweg 55, 2333 CC Leiden , The Netherlands

Cited by 70 stored of 70

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References 76