Oral Administration of an Active Form of Vitamin D3 (Calcitriol) Decreases Atherosclerosis in Mice by Inducing Regulatory T Cells and Immature Dendritic Cells With Tolerogenic Functions

Objective-To determine whether the administration of an active form of vitamin D-3 (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. Methods and Results-Recent clinical studies have shown that lack of vitamin D-3 is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4(+) T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3(+) regulatory T cells and a decrease in CD80(+) CD86(+) dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol-treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c(+) DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell-dependent manner but also partly because of a decrease in DC maturation. Conclusion-Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis. (Arterioscler Thromb Vasc Biol. 2010;30:2495-2503.)