B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.

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Serval ID
serval:BIB_2293A4C0EF66
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.
Journal
Circulation
Author(s)
Tsiantoulas D., Sage A.P., Göderle L., Ozsvar-Kozma M., Murphy D., Porsch F., Pasterkamp G., Menche J., Schneider P., Mallat Z., Binder C.J.
ISSN
1524-4539 (Electronic)
ISSN-L
0009-7322
Publication state
Published
Issued date
13/11/2018
Peer-reviewed
Oui
Volume
138
Number
20
Pages
2263-2273
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe <sup>-/-</sup> and Ldlr <sup>-/-</sup> 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.
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.
These data identify a novel B cell-independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications.
Keywords
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, Mice, Mice, Inbred C57BL, Mice, Knockout, 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, Transmembrane Activator and CAML Interactor Protein, atherosclerosis, inflammation
Pubmed
Web of science
Open Access
Yes
Create date
15/06/2018 18:03
Last modification date
04/10/2019 6:08
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