Abstract 101: B1b Cell Homeostasis Is Maintained By Cd40 In Atherosclerosis
| Autor: | Myrthe E Reiche, Oom Pattarabajinard, Aditi Upadhye, Kikkie Poels, Claudia van Tiel, Stephen G Malin, Christoph J Binder, Norbert Gerdes, Christian Weber, Dorothee Atzler, Coleen A McNamara, Esther Lutgens |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 41 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Background: The co-stimulatory CD40-CD40L dyad is an important driver of atherosclerosis. CD40 exerts divergent, cell-specific roles, which differentially impacts atherogenesis. Objectives: We here investigate the role of the most prominent CD40-expressing cell type, the CD40 + B cell, in atherosclerosis. Methods: B cell subset specific CD40-expression of patients with mild and severe coronary artery disease (CAD) was determined by mass-cytometry and correlated to CAD severity. Underlying mechanisms were revealed using CD19-CD40 flfl -ApoE -/- (CD40 BKO ) and CD40 flfl -ApoE -/- (CD40 BWT ) mice. Results: Patients with severe CAD had similar CD40 expression levels on most B cell subsets but showed a profound decrease in CD40 on B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40 BKO mice exhibited an increased plaque area and a more advanced stage of atherosclerosis. Absence of B cell CD40 caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgM and (anti-ox/MDA-LDL) IgG. Interestingly, transcriptomics analysis revealed that the absence of CD40 on B1b cells in particular, caused altered gene expression pathways related to lipid uptake ( Cd36, Ldlr ), cellular stress and metabolism ( Nr4a1, Hif1a ), and cell death ( Naip5/6, Top1 ). Indeed, in vitro analysis showed that B1b CD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Finally, transfer of wild-type B1b cells into CD40 BKO mice prevented the increase in atherosclerosis. Conclusions: We here show that CD40 is a critical modulator of B1 cell protective function in hypercholesterolemia and atherosclerosis. |
| Databáze: | OpenAIRE |
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