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 ϩ T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3 ϩ regulatory T cells and a decrease in CD80 ϩ CD86 ϩ 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. CD11cϩ 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. , is a secosteroid hormone that not only plays a central role in bone and calcium metabolism but also modulates the immune response. Recent epidemiological studies have shown a relationship between low plasma levels of vitamin D 3 and a predisposition to cardiovascular events. [1][2][3] This finding is supported by a meta-analysis showing that oral vitamin D 3 treatment contributes to the improvement of mortality from all causes, in part by decreasing cardiovascular deaths. 4 Transgenic rats constitutively expressing vitamin D-24-hydroxylase, a model of vitamin D 3 deficiency, showed aggravated atherosclerosis under a high-fat and high-cholesterol diet, when compared with control rats. 5 However, there are no reports about the direct effects of an orally administered active form of vitamin D 3 on atherosclerosis. Conclusion-Oral See accompanying article on page 2317It is widely recognized that atherosclerosis is a complex inflammatory disease of the arterial wall, 6,7 in which the T-lymphocyte-mediated pathogenic immune response plays a critical role. Clinical strategies developed to modulate the immune response have been insufficient for preventing atherosclerosis. Cumulative data based on experimental animal models suggest that CD4 ϩ T cells are present within plaques from the initial stages of the disease in mice, and adaptive transfer of these cells is potentially proatherogenic. 8 Accumulating evidence has revealed novel functions of several subsets of regulatory T cells (Tregs), which maintain immunologic tolerance to self-antigens and inhibit atherosclerosis development by suppressing the inflammatory response of effector T cells. 9 -12 These studies have provided new insights into the immunopathogenesis of atherosclerosis and imply that promotion of regulatory immune responses may have therapeutic potential for suppression of atherosclerotic diseases.In addition to Tregs, dendritic cells (DCs) are al...

Dendritic Cells in Atherogenesis: Possible Novel Targets for Prevention of Atherosclerosis

“…The active form of vitamin D3, 1, 25(OH)2-dihydroxyvitamin D3 (calcitriol), and its analogue inhibited autoimmune disease in animal models via inducing tolerogenic DCs and Tregs [20][21][22][23] . Similar to these studies, for the first time, we demonstrated the beneficial effects of orally administrated calcitriol on atherosclerosis in apolipoprotein E-knockout (ApoE −/− ) mice by inducing Tregs and tolerogenic DCs 24) . Considering the strategy to prevent atherosclerosis by inducing Tregs and tolerogenic DCs, our group has focused on the intestinal immune system as a therapeutic target.…”

“…Importantly, this dose did not affect calcium metabolism in our study. A significant increase in CD4 ＋ T cells within plaques, compared with the control group 24) . Interestingly, immunohistochemical analyses of atherosclerotic lesions indicated a significantly increased number of Foxp3 ＋ Tregs and decreased number of CD11c ＋…”

“…Murine studies demonstrated that calcitriol and its analog have a beneficial effect in many animal models of acute colitis 20) , allergy 21) , and autoimmune disease, including diabetes 22) and psoriasis 23) . Given this background, we hypothesized that the induction of Tregs and tolerogenic DCs by oral calcitriol treatment can inhibit atherosclerosis in ApoE −/− mice 24) .…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…108 The (1,25-dihydroxycholecalciferol), an active form of vitamin D3, 124 and vaccination) limit inflammation and the development of atherosclerosis.…”

Dendritic Cells and Regulatory T Cells in Atherosclerosis

“…Oral administration of the active form of vitamin D3 (calcitriol) was found to induce tolerogenic DCs and Treg cells, leading to the attenuation of atherosclerosis in mice (Takeda et al, 2010). In addition, the administration of DCs pulsed with oxidized low density lipoprotein (LDL) to mice deficient in LDL receptors reduced atherosclerosis and increased plaque stability (Habets et al, 2010).…”