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Circulation. 2018 Jun 1. pii: CIRCULATIONAHA.117.032790. doi: 10.1161/CIRCULATIONAHA.117.032790. [Epub ahead of print]

BAFF Neutralization Aggravates Atherosclerosis.

Author information

1
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria & CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
3
University Medical Center Utrecht, Utrecht, Netherlands.
4
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
5
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
6
Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK & Institut National de la Sarche Médicale, Paris, France.
7
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria & CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria christoph.binder@meduniwien.ac.at.

Abstract

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.

KEYWORDS:

B cell activating factor (BAFF); B cells; Inflammation; Transmembrane activator and CAML interactor (TACI); atherosclerosis

PMID:
29858401
PMCID:
PMC6181204
[Available on 2019-12-01]
DOI:
10.1161/CIRCULATIONAHA.117.032790

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