Authors: Dimitrios Tsiantoulas, Andrew P. Sage, Laura Göderle, Maria Ozsvar-Kozma, Deirdre Murphy, Florentina Porsch, Gerard Pasterkamp, Jörg Menche, Pascal Schneider, Ziad Mallat, Christoph J. Binder
Summary: 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: To investigate the effect of BAFF neutralization in atherosclerosis, we treated Apoe-/- and Ldlr-/- mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, we studied atherosclerosis-prone mice that lack the alternative receptor for BAFF, transmembrane activator and CAML interactor (TACI).
Results: We 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 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.
Source: Circulation, 2018