Molecular Mechanisms of Vitamin D-Mediated Immunomodulation
DOI:
https://doi.org/10.31661/gmj.v10i.2097Keywords:
Vitamin D; Immunomodulation; Innate Immunity; Adaptive ImmunityAbstract
Ever since discovering the fat-soluble secosteroid vitamin D, an abundance of research has been conducted on the molecular mechanisms for the multiple health benefits of this nutrient. Studies on the beneficial effects of vitamin D supplementation have found appreciable evidence suggesting that it may play a more prime role than initially presumed. Though it has largely been implicated in bone pathophysiology, novel research on vitamin D indicates its fundamental involvement in a wide range of disease processes through its multiple systemic effects, including but not limited to metabolic, cardiovascular, anti-inflammatory, antineoplastic, antioxidant, neuroprotective, and immune actions. Recent work has yielded important mechanistic insights into the functions of vitamin D in mediating immunity. The present work sheds light on the metabolism and immune response mechanisms of vitamin D. Current review is based on a thorough search of the available relevant research findings of the metabolic transformations of vitamin D and the molecular basis of its role in immunity. Apart from its classical mechanistic control of mineral homeostasis, vitamin D has immunomodulatory effects through various mechanisms at both systemic and cellular levels. Disruption of vitamin D reliant molecular pathways in the regulation of immune response can potentially result in the development and/or progression of autoimmune and infective processes. [GMJ.2021;10:e2097]
References
Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008;88:491S-9S. https://doi.org/10.1093/ajcn/88.2.491SPMid:18689389 Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012;523(1):123-33. https://doi.org/10.1016/j.abb.2012.04.001PMid:22503810 Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-29. https://doi.org/10.1016/j.chembiol.2013.12.016PMid:24529992 PMCid:PMC3968073 Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73-8. https://doi.org/10.1016/j.annepidem.2007.12.001PMid:18329892 PMCid:PMC2665033 Bikle DD, Schwartz J. Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions. Front Endocrinol (Lausanne). 2019;10:317. https://doi.org/10.3389/fendo.2019.00317PMid:31191450 PMCid:PMC6546814 Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, et al. International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol Rev. 2006;58(4):742-59. https://doi.org/10.1124/pr.58.4.6PMid:17132852 Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, et al. The Spl transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7. Genomics. 1991;11:168-73. https://doi.org/10.1016/0888-7543(91)90114-T Cui X, Gooch H, Petty A, McGrath JJ, Eyles D. Vitamin D and the brain: Genomic and non-genomic actions. Mol Cell Endocrinol. 2017;453:131-43. https://doi.org/10.1016/j.mce.2017.05.035PMid:28579120 Hii CS, Ferrante A. The Non-Genomic Actions of Vitamin D. Nutrients. 2016;8(3):135. https://doi.org/10.3390/nu8030135PMid:26950144 PMCid:PMC4808864 Christakos S. Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption. Rev Endocr Metab Disord. 2012;13(1):39-44. https://doi.org/10.1007/s11154-011-9197-xPMid:21861106 Diaz de Barboza G, Guizzardi S, Tolosa de Talamoni N. Molecular aspects of intestinal calcium absorption. World J Gastroenterol. 2015;21(23):7142-54. https://doi.org/10.3748/wjg.v21.i23.7142PMid:26109800 PMCid:PMC4476875 Kido S, Kaneko I, Tatsumi S, Segawa H, Miyamoto K. Vitamin D and type II sodium-dependent phosphate cotransporters. Contrib Nephrol. 2013;180:86-97. https://doi.org/10.1159/000346786PMid:23652552 Hattenhauer O, Traebert M, Murer H, Biber J. Regulation of small intestinal Na-Pi type IIb cotransporter by dietary phosphate intake. Am J Physiol. 1999;277:G756-G62. https://doi.org/10.1152/ajpgi.1999.277.4.G756PMid:10516141 Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol. 2015;10(7):1257-72. https://doi.org/10.2215/CJN.09750913PMid:25287933 PMCid:PMC4491294 Kurnik BRC, Hruska KA. Mechanism of stimulation of renal phosphate transport by 1,25-dihydroxycholecaiciferol. Biochimica et Biophysica Acta. 1985;817:42-50. https://doi.org/10.1016/0005-2736(85)90066-5 Yamamoto Y, Yoshizawa T, Fukuda T, Shirode-Fukuda Y, Yu T, Sekine K, et al. Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology. 2013;154(3):1008-20. https://doi.org/10.1210/en.2012-1542PMid:23389957 Yoshida T, Stern PH. How vitamin D works on bone. Endocrinol Metab Clin North Am. 2012;41(3):557-69. https://doi.org/10.1016/j.ecl.2012.04.003PMid:22877429 Khundmiri SJ, Murray RD, Lederer E. PTH and Vitamin D. Compr Physiol. 2016;6(2):561-601. https://doi.org/10.1002/cphy.c140071PMid:27065162 Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012;71(1):50-61. https://doi.org/10.1017/S0029665111001650PMid:21849106 Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013;5(7):2502-21. https://doi.org/10.3390/nu5072502PMid:23857223 PMCid:PMC3738984 Djukic M, Onken ML, Schutze S, Redlich S, Gotz A, Hanisch UK, et al. Vitamin d deficiency reduces the immune response, phagocytosis rate, and intracellular killing rate of microglial cells. Infect Immun. 2014;82(6):2585-94. https://doi.org/10.1128/IAI.01814-14PMid:24686054 PMCid:PMC4019194 Lang PO, Aspinall R. Vitamin D status and the host resistance to infections: What it is currently (not) understood. Clin Ther. 2017;39(5):930-45. https://doi.org/10.1016/j.clinthera.2017.04.004PMid:28457494 Gunville CF, Mourani PM, Ginde AA. The role of vitamin D in prevention and treatment of infection. Inflamm Allergy Drug Targets. 2013;12(4):239-45. https://doi.org/10.2174/18715281113129990046PMid:23782205 PMCid:PMC3756814 Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629-37. https://doi.org/10.1001/archinte.168.15.1629PMid:18695076 PMCid:PMC2677029 Bordon Y. Asthma and allergy: Vitamin D primes neonatal immune system. Nat Rev Immunol. 2017;17(8):467. https://doi.org/10.1038/nri.2017.82 Alswailmi FK, Sikandar MZ, Shah SIA. Biological roles of vitamin D and immunoglobulin E: Implications in allergic disorders. Pak J Med Health Sci. 2020;14(3):495-8. Alswailmi FK, Shah SIA, Nawaz H. Immunomodulatory role of vitamin D: Clinical implications in infections and autoimmune disorders. Gomal J Med Sci. 2020;18(3):132-8. https://doi.org/10.46903/gjms/18.03.841 Shah SIA. Beneficial role of vitamin D in common cancers: Is the evidence compelling enough? World Cancer Res J. 2020;7:e1574. Shalayel MH, Al-Mazaideh GM, Aladaileh SH, Alswailmi FK, Al-Thiabat MG. Vitamin D is a potential inhibitor of COVID-19: In silico molecular docking to the binding site of SARS-CoV-2 endoribonuclease Nsp15. Pak J Pharm Sci. 2020;33(5):2179-86. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22(2):240-73, Table of Contents. https://doi.org/10.1128/CMR.00046-08PMid:19366914 PMCid:PMC2668232 Suresh R, Mosser DM. Pattern recognition receptors in innate immunity, host defense, and immunopathology. Adv Physiol Educ. 2013;37(4):284-91. https://doi.org/10.1152/advan.00058.2013PMid:24292903 PMCid:PMC4089092 Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-76. https://doi.org/10.1146/annurev.immunol.21.120601.141126PMid:12524386 Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol. 2014;5:151. https://doi.org/10.3389/fphys.2014.00151PMid:24795646 PMCid:PMC4000998 Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM. Vitamin D and immune system. Vitam Miner. 2017;6(1):1000151. Wang TT, Dabbas B, Laperriere D, Bitton AJ, Soualhine H, Tavera-Mendoza LE, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J Biol Chem. 2010;285(4):2227-31. https://doi.org/10.1074/jbc.C109.071225PMid:19948723 PMCid:PMC2807280 Hoyer-Hansen M, Bastholm L, Mathiasen IS, Elling F, Jaattela M. Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ. 2005;12(10):1297-309. https://doi.org/10.1038/sj.cdd.4401651PMid:15905882 Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K, et al. Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol. 2014;25(3):564-72. https://doi.org/10.1681/ASN.2013040355PMid:24204002 PMCid:PMC3935584 Cross JH, Bradbury RS, Fulford AJ, Jallow AT, Wegmuller R, Prentice AM, et al. Oral iron acutely elevates bacterial growth in human serum. Sci Rep. 2015;5:16670. https://doi.org/10.1038/srep16670PMid:26593732 PMCid:PMC4655407 Harle D, Radmark O, Samuelsson B, Steinhilber D. Calcitriol and transforming growth factor-β upregulate 5-lipoxygenase mRNA expression by increasing gene transcription and mRNA maturation. Eur J Biochem. 1998;254:275-81. https://doi.org/10.1046/j.1432-1327.1998.2540275.xPMid:9660180 Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2006;36(2):361-70. https://doi.org/10.1002/eji.200425995PMid:16402404 Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275-306. https://doi.org/10.1146/annurev.immunol.23.021704.115633PMid:15771572 Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685-711. https://doi.org/10.1146/annurev.immunol.21.120601.141040PMid:12615891 Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, et al. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol. 2003;170(11):5382-90. https://doi.org/10.4049/jimmunol.170.11.5382PMid:12759412 Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am. 2010;39(2):365-79, table of contents. https://doi.org/10.1016/j.ecl.2010.02.010PMid:20511058 PMCid:PMC2879394 Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr. 1995;125(6 Suppl):1704S-8S. https://doi.org/10.1016/0960-0760(95)00106-A Colin EM, Asmawidjaja PS, van Hamburg JP, Mus AM, van Driel M, Hazes JM, et al. 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum. 2010;62(1):132-42. https://doi.org/10.1002/art.25043PMid:20039421 Korn T, Oukka M, Kuchroo V, Bettelli E. Th17 cells: effector T cells with inflammatory properties. Semin Immunol. 2007;19(6):362-71. https://doi.org/10.1016/j.smim.2007.10.007PMid:18035554 PMCid:PMC2839934 Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem. 2010;285(50):38751-5. https://doi.org/10.1074/jbc.C110.185777PMid:20974859 PMCid:PMC2998156 Urry Z, Xystrakis E, Richards DF, McDonald J, Sattar Z, Cousins DJ, et al. Ligation of TLR9 induced on human IL-10-secreting Tregs by 1alpha,25-dihydroxyvitamin D3 abrogates regulatory function. J Clin Invest. 2009;119(2):387-98. https://doi.org/10.1172/JCI32354PMid:19139565 PMCid:PMC2631286 Adorini L, Penna G, Giarratana N, Roncari A, Amuchastegui S, Daniel KC, et al. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol. 2004;89-90(1-5):437-41. https://doi.org/10.1016/j.jsbmb.2004.03.013PMid:15225816 Cheroutre H, Lambolez F. Doubting the TCR coreceptor function of CD8alphaalpha. Immunity. 2008;28(2):149-59. https://doi.org/10.1016/j.immuni.2008.01.005PMid:18275828 Yu S, Bruce D, Froicu M, Weaver V, Cantorna MT. Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice. Proc Natl Acad Sci U S A. 2008;105(52):20834-9. https://doi.org/10.1073/pnas.0808700106PMid:19095793 PMCid:PMC2634903 Sakem B, Nock C, Stanga Z, Medina P, Nydegger UE, Risch M, et al. Serum concentrations of 25-hydroxyvitamin D and immunoglobulins in an older Swiss cohort: results of the Senior Labor Study. BMC Med. 2013;11:176. https://doi.org/10.1186/1741-7015-11-176PMid:23902738 PMCid:PMC3751655 Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179(3):1634-47. https://doi.org/10.4049/jimmunol.179.3.1634PMid:17641030
