B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.
Wolters Kluwer Health
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Tsiantoulas, D., Sage, A., Göderle, L., Ozsvar-Kozma, M., Murphy, D., Porsch, F., Pasterkamp, G., et al. (2018). B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.. Circulation, 138 (20), 2263-2273. https://doi.org/10.1161/circulationaha.117.032790
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 receptor (BAFFR) 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 BAFFR 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 and Results: We demonstrate here that treatment with a well-characterized blocking antibody against BAFF increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell specific deletion of an alternative receptor for BAFF, transmembrane activator and CAML interactor receptor (TACI), also results in increased atherosclerosis, while B cell-specific TACI deletion had no effect. Mechanistically, BAFF-TACI signaling represses macrophage IRF7-dependent (but not NF-kB dependent) TLR9 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.
Aorta, Bone Marrow Cells, Macrophages, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Cholesterol, Antibodies, Immunotherapy, Atherosclerosis, Interferon Regulatory Factor-7, Toll-Like Receptor 9, Chemokine CCL2, B-Cell Activating Factor, Transmembrane Activator and CAML Interactor Protein, Chemokine CXCL10
This work was supported by grants of the Austrian Science Fund (SFB F54), the European Union (FP7 VIA), the British Heart Foundation, and the European Research Council (ERC). PS is supported by grants from the Swiss National Science Foundation.
British Heart Foundation (RG/10/001/27643)
British Heart Foundation (CH/10/001/27642)
British Heart Foundation (FS/15/57/31557)
European Research Council (281164)
EC FP7 CP (603131)
British Heart Foundation (RG/15/11/31593)
External DOI: https://doi.org/10.1161/circulationaha.117.032790
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283298
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/