Cardiovascular Research Advance Access first published online on August 30, 2009
This version [Corrected Proof] published online on September 19, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp300
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Inhibition of arterial lesion progression in CD16-deficient mice: evidence for altered immunity and the role of IL-10
1 Veterans Affairs Medical Center, Code 151, VAM&ROC, 215 N. Main Street, White River Junction, VT 05009, USA
2 Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA
3 Division of Endocrinology and Metabolism, University of California-San Diego, San Diego, CA, USA
4 Department of Pathology, University of Vermont, Burlington, VT, USA
5 Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
* Corresponding author. Tel: +1 802 295 9363, ext. 5895, Fax: +1 802 296 6308, Email: peter.morganelli{at}dartmouth.edu
Aims: Given the importance of IgG Fc receptors in immune regulation, we hypothesized that Fcg receptor type III (FcgRIII, CD16) plays an important role in atherogenesis. We therefore analysed the formation of arterial lesions in LDL receptor-deficient (LDLR–/–) and FcgRIII–/–xLDLR–/– double knockout mice at three different points up to 24 weeks of exposure to a high-fat diet.
Methods and results: Analysis of Oil Red-O-stained sections revealed no difference in lesion formation between strains after 6 weeks of a high-fat diet, and a modest decrease after 14 weeks in double knockouts relative to LDLR–/– controls. After 24 weeks, lesion formation was decreased in the aortic root (30%) and innominate artery (50%) in FcgRIII double knockouts relative to LDLR–/– controls. Analysis of peripheral CD4+ T-cells by intracellular flow cytometry from double knockouts after 24 weeks of a high-fat diet revealed statistically significant increases in the percentages of cells producing interferon-
, interleukin (IL)-10, and IL-4 relative to controls, differences that were also observed by analyses of whole aortas for cytokine mRNA levels. As determined by flow cytometry, FcgRIII deficiency resulted in an expansion of CD4+ cells and an increase in the CD4 to CD8 ratio. Analysis of plasma anti-oxidized LDL (OxLDL) antibodies by chemiluminescent assay revealed that IgG1 and IgG2c titers to OxLDL were increased in FcgRIII –/–xLDLR–/– double knockouts relative to LDLR–/– controls, while total IgG levels were similar.
Conclusion: These results reveal altered immunity in FcgRIII–/–xLDLR–/– mice and a reduction in lesion formation associated with increased production of IL-10 by an expansion of CD4+ T-cells. The reduction in lesion formation was manifest well after evidence of an immune response to OxLDL, suggesting that FcgRIII contributes to lesion progression in murine atherosclerosis.
KEYWORDS Fc receptors; CD16; Murine atherosclerosis; T-cells; Oxidized LDL; Lesions; IL-10; Interferon; Lymphoid follicle
Time for primary review: 36 days