Open AccessCombined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice
Author(s) -
Fei Cheng,
Laura Twardowski,
Kurt Reifenberg,
Kerstin Winter,
Antje Canisius,
Eva Proß,
Jianglin Fan,
Edgar Schmitt,
Leonard D. Shultz,
Karl J. Lackner,
Michael Torzewski
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0157311
Subject(s) - ldl receptor , recombination activating gene , immune system , biology , balb/c , immunology , cholesterol , medicine , endocrinology , lipoprotein , recombination , biochemistry , gene
This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C- Ldlr -/- Rag1 -/- mice, which show severe combined B- and T-cell immunodeficiency and C- Ldlr -/- Rag1 -/- Il2rg -/- mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western type diet (WTD). Both B6- Ldlr -/- and C- Ldlr -/- immunocompetent mice were used as controls. Body weights and serum cholesterol levels of both immunodeficient strains were significantly increased compared to C- Ldlr -/- controls, except for cholesterol levels of C- Ldlr -/- Rag1 -/- double mutants after 12 weeks on the WTD. Quantification of the aortic sinus plaque area revealed that both strains of immunodeficient mice developed significantly more atherosclerosis compared to C- Ldlr -/- controls after 24 weeks on the WTD. Increased atherosclerotic lesion development in C- Ldlr -/- Rag1 -/- Il2rg -/- triple mutants was associated with significantly increased numbers of macrophages and significantly decreased numbers of smooth muscle cells compared to both C- Ldlr -/- wild type and C- Ldlr -/- Rag1 -/- double mutants pointing to a plaque destabilizing effect of NK cell loss. Collectively, the present study reveals a previously unappreciated complexity with regard to the impact of lymphocytes on lipoprotein metabolism and the role of lymphocyte subsets in plaque composition.