Leukocyte Bim deficiency does not impact atherogenesis in ldlr -/- mice, despite a pronounced induction of autoimmune inflammation
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Date
2017-06-08
Authors
Temmerman, Lieve
Westra, Marijke M.
Bot, Ilze
van Vlijmen, Bart J. M.
Van Bree, Niek
Bot, Martine
Habets, Kim L. L.
Keulers, Tom G. H.
van der Vlag, Johan
Cotter, Thomas G.
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Publishing Group
Published Version
Abstract
Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim−/− or wild type bone marrow transplanted ldlr−/− mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed. Bim−/− transplanted mice displayed splenomegaly and overt lymphocytosis. CD4+ and CD8+ T cells were more activated (increased CD69 and CD71 expression, increased interferon gamma production). B cells were elevated by 147%, with a shift towards the pro-atherogenic IgG-producing B2 cell phenotype, resulting in a doubling of anti-oxLDL IgG1 antibody titers in serum of bim−/− mice. Bim−/− mice displayed massive intraplaque accumulation of Ig complexes and of lesional T cells, although this did not translate in changes in plaque size or stability features (apoptotic cell and macrophage content). The surprising lack in plaque phenotype despite the profound pro-atherogenic immune effects may be attributable to the sharp reduction of serum cholesterol levels in WTD fed bim−/− mice.
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Keywords
Atherosclerosis , Autoimmunity , Chronic inflammation , Experimental models of disease
Citation
Temmerman, L., Westra, M. M., Bot, I., Vlijmen, B. J. M. v., Bree, N. V., Bot, M., Habets, K. L. L., Keulers, T. G. H., Vlag, J. v. d., Cotter, T. G., Berkel, T. J. C. v. and Biessen, E. A. L. (2017) 'Leukocyte Bim deficiency does not impact atherogenesis in ldlr −/− mice, despite a pronounced induction of autoimmune inflammation', Scientific Reports, 7(1), 3086. doi:10.1038/s41598-017-02771-4