Single-cell profiling reveals age-associated immunity in atherosclerosis

免疫衰老 免疫学 生物 免疫系统 CD11c公司 T细胞 CD8型 抗原 医学 表型 基因 生物化学
作者
Virginia Smit,Jill de Mol,Frank H. Schaftenaar,Marie A.C. Depuydt,Rimke J. Postel,Diede Smeets,Frans W. Verheijen,Laurens Bogers,Janine van Duijn,Robin A.F. Verwilligen,Hendrika W. Grievink,Mireia N. A. Bernabé Kleijn,Eva van Ingen,Maaike J.M. de Jong,Lauren Goncalves,Judith A. H. M. Peeters,H.J. Smeets,Anouk Wezel,Julia K. Polansky,Menno P.J. de Winther,Christoph J. Binder,Dimitrios Tsiantoulas,Ilze Bot,Johan Kuiper,Amanda C. Foks
出处
期刊:Cardiovascular Research [Oxford University Press]
卷期号:119 (15): 2508-2521 被引量:21
标识
DOI:10.1093/cvr/cvad099
摘要

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.
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