B Cell-Activating Factor Neutralization Aggravates Atherosclerosis
Autor: | Tsiantoulas, Dimitrios, Sage, Andrew P, Göderle, Laura, Ozsvar-Kozma, Maria, Murphy, Deirdre, Porsch, Florentina, Pasterkamp, Gerard, Menche, Jörg, Schneider, Pascal, Mallat, Ziad, Binder, Christoph J |
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Přispěvatelé: | Sage, Andrew [0000-0001-7255-3497], Mallat, Ziad [0000-0003-0443-7878], Apollo - University of Cambridge Repository |
Rok vydání: | 2018 |
Předmět: |
Mice
Knockout Macrophages Interferon Regulatory Factor-7 Transmembrane Activator and CAML Interactor Protein Bone Marrow Cells Atherosclerosis Antibodies Chemokine CXCL10 Mice Inbred C57BL Mice Cholesterol Animals Antibodies/immunology Antibodies/therapeutic use Aorta/pathology Atherosclerosis/therapy B-Cell Activating Factor/immunology Bone Marrow Cells/cytology Chemokine CCL2/genetics Chemokine CCL2/metabolism Chemokine CXCL10/genetics Chemokine CXCL10/metabolism Cholesterol/blood Immunotherapy Interferon Regulatory Factor-7/metabolism Macrophages/cytology Macrophages/metabolism Toll-Like Receptor 9/metabolism Transmembrane Activator and CAML Interactor Protein/genetics Transmembrane Activator and CAML Interactor Protein/metabolism B-cell activating factor B-lymphocytes atherosclerosis inflammation Toll-Like Receptor 9 Original Research Articles B-Cell Activating Factor ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Aorta Chemokine CCL2 |
Zdroj: | Circulation Circulation, vol. 138, no. 20, pp. 2263-2273 |
ISSN: | 1524-4539 |
Popis: | Supplemental Digital Content is available in the text. Background: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell–activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. Methods: To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe−/− and Ldlr−/− mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, the authors studied atherosclerosis-prone mice that lack the alternative receptor for BAFF: transmembrane activator and calcium modulator and cyclophilin ligand interactor. Results: The authors demonstrate here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell–specific deletion of transmembrane activator and calcium modulator and cyclophilin ligand interactor also results in increased atherosclerosis, while B cell–specific transmembrane activator and calcium modulator and cyclophilin ligand interactor deletion had no effect. Mechanistically, BAFF–transmembrane activator and calcium modulator and cyclophilin ligand interactor signaling represses macrophage IRF7-dependent (but not NF-κB–dependent) Toll-like receptor 9 responses including proatherogenic CXCL10 production. Conclusions: These data identify a novel B cell–independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications. |
Databáze: | OpenAIRE |
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