Abstract 195: Apolipoprotein E Suppresses Atherosclerosis by Reducing Th1 Inflammatory Responses and by Favorably Altering Aortic Dendritic Cell Subsets in Hyperlipidemic Mice
Apolipoprotein (apo) E can suppress atherosclerosis by regulating myeloid cell proliferation and monocyte activation. However, little is known about its capacity to regulate adaptive immunity. To explore this question, we studied our recently described HypoE mice deficient in the LDL receptor (Apoeh/hLdlr−/− mice) that spontaneously develop a hyperlipidemia similar to that of Apoe-/-Ldlr-/- mice when fed a chow diet, but accumulate apoE in plasma and display reduced atherosclerosis. Twenty-week old Apoeh/hLdlr-/- mice (n=10) displayed smaller spleen and lymph nodes that contained fewer leukocytes (p<0.05) and (p<0.0001) respectively compared to Apoe-/-Ldlr-/- mice (n=8). Both myeloid-derived and lymphoid-derived cell counts were decreased in the spleen of Apoeh/hLdlr-/- mice. Further analysis showed that both the spleens and lymph nodes of Apoeh/hLdlr-/- mice had a higher percentage of T cells that displayed a naïve phenotype (CD44lowCD62Lhigh) compared to Apoe-/-Ldlr-/- mice. In contrast, the percentage of memory effector T cells (CD44highCD62Llow) was decreased in Apoeh/hLdlr-/- mice. Intracellular cytokine analysis showed that both CD4+ (p<0.01) and CD8+ (p<0.05) T cells in spleens derived from Apoeh/hLdlr-/- mice produced 50% less IFN-γ than those of Apoe-/-Ldlr-/- mice. Reduced T cell activation and Th1 differentiation did not derive from enhanced Foxp3+ regulatory T cell (Tregs) function as the frequency and suppressive function of Tregs isolated from Apoeh/hLdlr-/- mice and Apoe-/-Ldlr-/- mice were similar at that time point. In marked contrast, DCs isolated from spleens of Apoeh/hLdlr-/- mice showed less expression of the co-stimulatory molecule CD86 compared to those of Apoe-/-Ldlr-/- mice. We also observed a significant decrease in both T cell (p<0.05) and DC numbers (p<0.01) in digested aortas of Apoeh/hLdlr-/- mice compared to those of Apoe-/-Ldlr-/- mice. Interestingly, aortic DCs derived from Apoeh/hLdlr-/- mice displayed a lower percentage of the pro-inflammatory CD11b+ subtype but a higher percentage of the anti-inflammatory CD103+ subtype. Collectively, our findings provide the first in-vivo evidence that apoE can suppress T cell activation and favorably alter DC subsets in the aorta of hyperlipidemic mice.
- © 2013 by American Heart Association, Inc.