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• W2154939970 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 30, No. 12Vitamin D3 Suppresses Immune Reactions in Atherosclerosis, Affecting Regulatory T Cells and Dendritic Cell Function Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBVitamin D3 Suppresses Immune Reactions in Atherosclerosis, Affecting Regulatory T Cells and Dendritic Cell Function Yuri V. Bobryshev Yuri V. BobryshevYuri V. Bobryshev From the Faculty of Medicine, University of New South Wales, Sydney, Australia. Search for more papers by this author Originally published1 Dec 2010https://doi.org/10.1161/ATVBAHA.110.217141Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:2317–2319Accumulated evidence indicates that 1,25-dihydroxyvitamin D3 (vitamin D3) plays important roles in bone and calcium metabolism and in immune processes.1–4 Several autoimmune disorders have been linked to a deficiency in vitamin D3.1–4 Epidemiological data indicate that vitamin D3 deficiency is associated with cardiovascular events.5,6See accompanying article on page 2495In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Takeda et al7 report the results of a study undertaken to analyze the mechanisms by which vitamin D3 might affect the development of atherosclerotic lesions. By using a mouse model, Takeda et al demonstrated that an orally administered active form of vitamin D3 (calcitriol) led to a marked reduction in atherosclerotic lesion formation. The study revealed that a reduction in atherosclerotic lesion formation occurred by the suppression of immune reactions, with at least 2 cell types crucially involved in vitamin D3 effects (ie, CD4+CD25+ Fork head box protein [Foxp] 3+ regulatory T cells [Tregs] and dendritic cells [DCs]).Tregs exert functions in the induction and maintenance of immune tolerance.8–11 The family of Tregs is represented by a heterogeneous cell population that includes adaptive and naturally occurring Tregs.8–11 According to the current paradigm, adaptive Tregs develop from naïve T cells in the periphery and can produce interleukin 10 and transforming growth factor β, whereas naturally occurring Tregs originate in the thymus as CD4+CD25+ cells and perform their suppressive functions through cell-to-cell contacts and membrane-bound transforming growth factor β and cytotoxic T-lymphocyte antigen-4 (CTLA-4).8–11 The transcription factor Foxp3 is necessary for the development of this subpopulation of CD25+ Tregs, being their characteristic marker.8–11 Mouse model studies have demonstrated that Tregs play a protective role against atherosclerosis, igniting interest in this cell type as a potential cell target in combating atherosclerosis.12 When analyzing atherosclerotic lesions of mice that received calcitriol orally, Takeda et al7 found that the lesions were characterized by a reduced accumulation of CD4+ cells and a significant increase in number of CD25+Foxp3+ Tregs (Figure). Neutralization of CD25 by injection of anti–CD25 antibody in mice indicated that the effects of vitamin D3 were mainly Foxp3+ Treg dependent.7Download figureDownload PowerPointFigure. Effects of vitamin D3 on Tregs and DCs in atherosclerotic arteries.In addition to Tregs, DCs have been involved in the initiation of immune reactions by stimulating differentiation of naïve T cells and maintaining tolerance to self-antigens.13–16 DCs populate atherosclerotic lesions in mice as in humans.17–19 Takeda et al7 undertook a comparative analysis of DC populations in atherosclerotic lesions in mice that received calcitriol and in control animals and found significant reductions in the number of CD86+ DCs in lesions.The activation of effector T cells in atherosclerosis critically depends on the ability of T cells to receive antigen that is presented in complex with antigen-presenting molecules, such as major histocompatibility complex class II displayed on the surface of antigen-presenting cells.13–16 As in other anatomic locations,13–16 antigen presentation in arteries is provided by DCs,17–19 which are the most powerful of antigen-presenting cells.13–16 In addition to the development of atherosclerotic lesions, normal arteries of mice contain immature DCs that are thought to develop from circulating DC precursors originating from bone marrow (Figure).17–19 In the arterial wall, immature DCs consistently test the surrounding microenvironment for the presence of “danger” signals.17–19 After engulfing antigen, recognized by an immature DC as a danger signal, the DC matures, involving a reduction in endocytotic activity and an increase in the expression of antigen-presenting molecules. Some DCs that mature are thought to migrate via the lymphatic vessels to regional lymph nodes, where contact with T cells occurs and leads to T-cell activation (Figure).17 Apart from this “classical” migratory route, some DCs, activated by danger signals, can be retained within the arterial wall and mature locally before forming direct contacts with T cells in situ, which leads to the activation of T cells within the arterial vessels (Figure).17–19The maturation of DCs is usually accompanied by the expression of costimulatory molecules (eg, CD40, CD80, and CD86) that are necessary for the activation of T cells in DC/T-cell contacts.13–19 However, in the absence of costimulation, T cells in DC/T-cell contacts undergo anergy or even apoptosis.14–16 Some immature (or semimature) DCs that lack expression of costimulatory molecules could become capable of forming contacts with T cells and, thus, these DCs acquire tolerogenic properties.14–16 A detailed analysis of atherosclerotic lesions in mice that received calcitriol orally allowed Takeda et al7 to conclude that these lesions contained increased numbers of immature DCs with tolerogenic functions (Figure). Although a clear understanding of the interplay of Tregs and DCs is yet to be established, accumulating data indicate that continuous cross talk between these 2 cell types occurs20–22 and might lead to the induction of Tregs by immature DCs with an insufficient expression of costimulatory molecules.20,21 In their turn, Tregs play a crucial role in DC differentiation and maturation.20,21 Direct effects of vitamin D3 on Tregs and DCs are recognized.23–25Takeda et al7 also examined the numbers and characteristics of Tregs and DCs in the small intestine, mesenteric lymph nodes, and spleen; and showed that oral administration of calcitriol affected immune reactions in atherosclerosis locally (within the arterial wall) and systemically, further supporting the suggestion that immune reactions occurring in the arterial wall are just the “tip of the iceberg.”26 The findings allowed Takeda et al to proffer the novel concept in cardiology that intestinal and arterial immunity are interconnected; they suggest that the intestinal immune system might be a novel therapeutic target for treatment of atherosclerosis.Accumulating knowledge has revealed that atherosclerosis is an autoimmune disease.27 The findings of the study by Takeda et al7 demonstrate a great similarity of immune mechanisms involved in atherosclerosis and other autoimmune disorders. As in the animal model examined by Takeda et al,7 Tregs and DCs are the major players in immune reactions in autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, and osteoporosis.8–11,14–16 In these autoimmune diseases, vitamin D3 supplementation may be beneficial or currently prescribed.1–4,23–25Despite the success from using statins, prevention of clinical events of atherosclerosis remains a major challenge.28 Immunization strategies directed against atherosclerosis-related antigens, such as epitopes within the low-density lipoprotein particle, develop rapidly28; obviously, it would take time to eventuate their clinical use. The enhancement of inherent atheroprotective immunity by expansion of the use of Tregs may emerge as an alternative therapeutic strategy.12,28 The work of Takeda et al7 should further promote interest in the use of vitamin D3 or vitamin D receptor agonists29 in the prevention and treatment of atherosclerosis.Sources of FundingThis study was supported by the School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.DisclosuresNone.FootnotesCorrespondence to Yuri V. Bobryshev, PhD, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Kensington, New South Wales 2052, Australia. E-mail [email protected] References 1 Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am. 2010; 39: 365–379.CrossrefMedlineGoogle Scholar2 Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010; 10: 482–496.CrossrefMedlineGoogle Scholar3 Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008; 87: 1080S–1086S.CrossrefMedlineGoogle Scholar4 Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab. 2010; 95: 471–478.CrossrefMedlineGoogle Scholar5 Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008; 117: 503–511.LinkGoogle Scholar6 Zittermann A, Koerfer R. Vitamin D in the prevention and treatment of coronary heart disease. Curr Opin Clin Nutr Metab Care. 2008; 11: 752–757.CrossrefMedlineGoogle Scholar7 Takeda M, Yamashita T, Sasaki N, Nakajima K, Kita T, Shinohara M, Ishida T, Hirata K. Oral administration of an active form vitamin D3 (calcitriol) decreases atherosclerosis in mice via inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arterioscler Thromb Vasc Biol. 2010; 30: 2495–2503.LinkGoogle Scholar8 Wan YY. Regulatory T cells: immune suppression and beyond. Cell Mol Immunol. 2010; 7: 204–210.CrossrefMedlineGoogle Scholar9 Sakaguchi S, Miyara M, Costantino CM, Hafler DA. Foxp3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010; 10: 490–500.CrossrefMedlineGoogle Scholar10 Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010; 11: 7–13.CrossrefMedlineGoogle Scholar11 Langier S, Sade K, Kivity S. Regulatory T cells: the suppressor arm of the immune system. Autoimmun Rev. Epub ahead of print August 31, 2010.Google Scholar12 Nilsson J, Wigren M, Shah PK. Regulatory T cells and the control of modified lipoprotein autoimmunity-driven atherosclerosis. Trends Cardiovasc Med. 2009; 19: 272–276.CrossrefMedlineGoogle Scholar13 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998; 392: 245–252.CrossrefMedlineGoogle Scholar14 Lotze MT, Thomson AW, eds. Dendritic Cells: Biology and Clinical Applications. 2nd ed. San Diego, CA: Academic Press; 2001.Google Scholar15 Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003; 21: 685–711.CrossrefMedlineGoogle Scholar16 Liu K, Nussenzweig MC. Development and homeostasis of dendritic cells. Eur J Immunol. 2010; 40: 2099–2102.CrossrefMedlineGoogle Scholar17 Bobryshev YV. Dendritic cells and their role in atherogenesis. Lab Invest. 2010; 90: 970–984.CrossrefMedlineGoogle Scholar18 Choi JH, Do Y, Cheong C, Koh H, Boscardin SB, Oh YS, Bozzacco L, Trumpfheller C, Park CG, Steinman RM. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med. 2009; 206: 497–505.CrossrefMedlineGoogle Scholar19 Cybulsky MI, Jongstra-Bilen J. Resident intimal dendritic cells and the initiation of atherosclerosis. Curr Opin Lipidol. 2010; 21: 397–403.CrossrefMedlineGoogle Scholar20 Yamazaki S, Steinman RM. Dendritic cells as controllers of antigen-specific Foxp3+ regulatory T cells. J Dermatol Sci. 2009; 54: 69–75.CrossrefMedlineGoogle Scholar21 Cobbold SP, Adams E, Nolan KF, Regateiro FS, Waldmann H. Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link. Immunol Rev. 2010; 236: 203–218.CrossrefMedlineGoogle Scholar22 van Es T, van Puijvelde GH, Foks AC, Habets KL, Bot I, Gilboa E, Van Berkel TJ, Kuiper J. Vaccination against Foxp3(+) regulatory T cells aggravates atherosclerosis. Atherosclerosis. 2010; 209: 74–80.CrossrefMedlineGoogle Scholar23 Adorini L, Giarratana N, Penna G. Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol. 2004; 16: 127–134.CrossrefMedlineGoogle Scholar24 van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005; 97: 93–101.CrossrefMedlineGoogle Scholar25 Sigmundsdottir H, Butcher EC. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat Immunol. 2008; 9: 981–987.MedlineGoogle Scholar26 Bobryshev YV. Dendritic cells and their involvement in atherosclerosis. Curr Opin Lipidol. 2000; 11: 511–517.CrossrefMedlineGoogle Scholar27 Nilsson J, Hansson GK. Autoimmunity in atherosclerosis: a protective response losing control? J Intern Med. 2008; 263: 464–478.CrossrefMedlineGoogle Scholar28 Klingenberg R, Hansson GK. Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J. 2009; 30: 2838–2844.CrossrefMedlineGoogle Scholar29 Wu-Wong JR. Potential for vitamin D receptor agonists in the treatment of cardiovascular disease. Br J Pharmacol. 2009; 158: 395–412.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Yevgi R, Bilge N, Simsek F, Eren A and Cimilli Senocak G (2021) Vitamin D levels and C-reactive protein/albumin ratio in pregnant women with cerebral venous sinus thrombosis, Journal of Thrombosis and Thrombolysis, 10.1007/s11239-021-02541-0, 53:2, (532-539), Online publication date: 1-Feb-2022. Radagdam S, Asoudeh-Fard A, Karimi M, Faridvand Y, Gholinejad Z and Gerayesh Nejad S (2021) Calcitriol modulates cholesteryl ester transfer protein (CETP) levels and lipid profile in hypercholesterolemic male rabbits: A pilot study, International Journal for Vitamin and Nutrition Research, 10.1024/0300-9831/a000613, 91:3-4, (212-216), Online publication date: 1-Jun-2021. 张 颖 (2018) Advance in Research on Vitamin D of Neurological Disease, Advances in Clinical Medicine, 10.12677/ACM.2018.82031, 08:02, (185-189), . 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McCullough P, McCullough W, Lehrer D, Travers J and Repas S (2021) Oral and Topical Vitamin D, Sunshine, and UVB Phototherapy Safely Control Psoriasis in Patients with Normal Pretreatment Serum 25-Hydroxyvitamin D Concentrations: A Literature Review and Discussion of Health Implications, Nutrients, 10.3390/nu13051511, 13:5, (1511) Adamczak D (2017) The Role of Toll-Like Receptors and Vitamin D in Cardiovascular Diseases—A Review, International Journal of Molecular Sciences, 10.3390/ijms18112252, 18:11, (2252) December 2010Vol 30, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/ATVBAHA.110.217141PMID: 21084698 Originally publishedDecember 1, 2010 Keywordsvitamin D3vascular biologyFoxp3atherosclerosisdendritic cellsregulatory T cellsPDF download Advertisement" @default.
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