Oral Administration of an Active Form of Vitamin D 3 (Calcitriol) Decreases Atherosclerosis in Mice by Inducing Regulatory T Cells and Immature Dendritic Cells With Tolerogenic Functions

Abstract

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.