Location: Arkansas Children's Nutrition CenterTitle: Attenuated atherosclerotic lesions in apoe-fc gamma-chain-deficient hyperlipidemic mouse model is associated with inhibition of Th17 cells and promotion of regulatory T cells Author
Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/23/2011
Publication Date: 12/1/2011
Citation: Ng, H., Burris, R.L., Nagarajan, S. 2011. Attenuated atherosclerotic lesions in apoe-fc gamma-chain-deficient hyperlipidemic mouse model is associated with inhibition of Th17 cells and promotion of regulatory T cells. Journal of Immunology. 187(11):6082-6093. Interpretive Summary: Atherosclerosis is a disease of the arteries characterized by the deposition of plaques of fatty material on their inner walls. There are several suspected causes of this disease, including genetics and lifestyle factors that lead to elevated low-density lipoprotein (LDL) which becomes oxidized to cause the plaques. Researchers at the Arkansas Children’s Nutrition Center have found that diets containing soy protein isolate can help prevent atherosclerotic lesions from forming in mouse models, but further studies are hampered by an inadequate understanding of the mechanisms by which the disease develops. In this study, the same researchers investigated the mechanisms by which atherosclerosis develops and using genetically modified mice, known as apoE-Fcgamma-chain double knockouts. They found that activating the receptor protein to which the apoE-Fcgamma protein binds is responsible for the generation of the immune response that leads to atherosclerosis. These data may be important in developing new measures to prevent atherosclerosis.
Technical Abstract: Though the presence of antioxidized low-density lipoprotein IgG is well documented in clinical and animal studies, the role for Fc gamma Rs to the progression of atherosclerosis has not been studied in detail. In the current study, we investigated the role for activating Fc gamma R in the progression of atherosclerosis using apolipoprotein E (apoE)-Fc gamma-chain double-knockout (DKO) mice. Relative to apoE knockout (KO) mice, arterial lesion formation was significantly decreased in apoE-Fc gamma-chain DKO mice. Bone marrow chimera studies showed reduced lesions in apoE KO mice receiving the bone marrow of apoE-Fc gamma-chain DKO mice. Compared to apoE KO mice, antioxidized low-density lipoprotein IgG1 (Th2) and IgG2a (Th1), IL-10, and IFN-gamma secretion by activated T cells was increased in apoE-Fc gamma-chain DKO mice. These findings suggest that reduced atherosclerotic lesion in apoE-Fc gamma-chain DKO mice is not due to a Th1/Th2 imbalance. Interestingly, the number of Th17 cells and the secretion of IL-17 by activated CD4(+) cells were decreased in apoE-Fc gamma-chain DKO mice. Notably, the number of regulatory T cells, expression of mRNA, and secretion of TGF-gamma and IL-10 were increased in apoE-Fc gamma-chain DKO mice. Furthermore, secretions of IL-6 and STAT-3 phosphorylation essential for Th17 cell genesis were reduced in apoE-Fc gamma-chain DKO mice. Importantly, decrease in Th17 cells in apoE-Fc gamma-chain DKO mice was due to reduced IL-6 release by APC of apoE-Fc gamma-chain DKO mice. Collectively, our data suggest that activating Fc gamma R promotes atherosclerosis by inducing a Th17 response in the hyperlipidemic apoE KO mouse model.