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B Cell-Activating Factor Neutralization Aggravates Atherosclerosis
Dimitrios Tsiantoulas1,2, Andrew P Sage3, Laura Göderle1,2
1Department of Laboratory Medicine, Medical University of Vienna (D.T., L.G., M.O.-K., F.P., C.J.B.).
Insights
Blocking B cell-activating factor (BAFF) therapy unexpectedly worsened atherosclerosis in mice by affecting myeloid cells, not B cells. This reveals a new anti-inflammatory role for BAFF independent of B cells, with potential clinical implications for cardiovascular disease.
Area of Science:
- Immunology
- Cardiovascular Science
- Genomics
Background:
- Atherosclerotic cardiovascular disease is a leading global cause of death, driven by arterial plaque buildup.
- Genomic studies implicate the B cell-activating factor (BAFF) pathway in coronary heart disease.
- Existing anti-BAFF therapies for autoimmune diseases suggest potential cardiovascular benefits, but direct effects on atherosclerosis are unknown.
Purpose of the Study:
- To investigate the impact of BAFF neutralization on atherosclerosis.
- To elucidate the mechanisms by which BAFF influences atherosclerosis progression.
Main Methods:
- Treatment of Apoe-/- and Ldlr-/- mice with an anti-BAFF antibody.
- Analysis of atherosclerosis-prone mice lacking the BAFF receptor, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).
- Investigation of myeloid cell-specific and B cell-specific TACI deletions.
Main Results:
- Anti-BAFF antibody treatment paradoxically increased atherosclerosis in mice, despite B cell depletion.
- Myeloid cell-specific TACI deletion, but not B cell-specific deletion, also increased atherosclerosis.
- BAFF-TACI signaling was found to suppress macrophage IRF7-dependent Toll-like receptor 9 responses and proatherogenic CXCL10 production.
Conclusions:
- BAFF plays a novel, B cell-independent anti-inflammatory role in atherosclerosis.
- These findings may have significant clinical implications for managing cardiovascular risk.
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.
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