5.1. Metabolism and Functions
Vitamin D is a fat-soluble hormone that is mainly synthesized in the skin after exposure to ultraviolet rays from sunlight (in the form of vitamin D3), and, to a lesser extent, is derived from dietary intake in the form of either vitamin D2 or D3 (the main sources of vitamin D are fatty fish, fish oils, egg yolks, cheese, and vitamin D-fortified foods). After vitamin D is produced in the skin or absorbed through the gastrointestinal tract, it is transported to the liver by vitamin D-binding protein (VDBP). In the liver vitamin D is converted to 25 hydroxy vitamin D (25(OH)D), which is monitored to evaluate vitamin D status because of its half-life of 2–3 weeks. Next, 25 hydroxy vitamin D is transported to the kidneys, where it is finally converted to its active form, 1,25 dihydroxyvitamin D (1,25(OH)2D).
The actions of 1,25(OH)2D are mediated through ligation with a nuclear vitamin D receptor (VDR), leading to the regulation of the transcription of over 1000 target genes. VDR is widely distributed in many different cells and tissues, including the immune system. VDR gene polymorphisms, located on chromosome 12q13.1, have been associated with higher prevalence of respiratory infections [74,75,76,77]. One of the main roles of vitamin D is to maintain calcium homeostasis by promoting calcium absorption in the intestine and reabsorption in the kidneys and stimulating bone remodeling by increasing osteoclasts number. This effect was the first to be discovered, studying the causes of rickets and osteomalacia, but now it is thought that vitamin D has physiological effects much broader that its role in mineral homeostasis and bone function [78], including regulation of immunity, fetal development [79], and pulmonary function [80]. In addition, vitamin D can also induce cathelicidin in gastrointestinal epithelium [81] and plays a role in controlling gastrointestinal infections [82].
For the purpose of this review, we focused on the effects of vitamin D in modulating the immune system. Several mechanisms have been described [83]: firstly, vitamin D was found to induce the production of antimicrobial peptides such as cathelicidin and human beta-defensin from immune system cells such as neutrophils and macrophages and from epithelial respiratory cells [81,82,83,84,85,86,87]. Vitamin D also enhances the antimicrobial activity of macrophages by increasing TLR and CD14 expression [88], autophagy [89,90], and the activity of NADPH-dependent oxidase [91]; it also promotes the migration of dendritic cells to lymphoid organs where they can present antigens to T cells [92]. On the other side of the coin, vitamin D can also inhibit the production of pro inflammatory cytokines, which might appear counterproductive [93]; it is known, however, that the pathogenicity of respiratory viruses, including SARS-CoV2, can be linked to hypercytokinemia up to the so-called “cytokine storm” [94,95,96,97,98]. This immunoregulatory effect of vitamin D can thus be beneficial to the host while facing a viral infection.
It has been reported during influenza A infection that IFN-beta, tumor necrosis factor (TNF)-alfa, IL-8 and IL-6 in the lungs were reduced in response to treatment with vitamin D [99]; during RSV infection the NfkB inhibitor was induced [100]; similar immunomodulatory effects were also described during Dengue infection [101]. Vitamin D can suppress excessive activity of IFN gamma-activated macrophages [102]; decrease macrophagic cytokines release through upregulation of MKP-1 [103]; reduce the production of metalloproteinase MMP-9 in keratinocytes, whose excessive and potentially harmful activity is induced by TNF alfa during hyperinflammation [104].
Vitamin D can also regulate FOXP3 expression in T cells, thus inducing the differentiation of this cells to FOXP3+ T regulatory cells (T reg), which have an immunosuppressor activity [105,106], and can promote the secretion of anti-inflammatory IL-10 from T cells [107]. It was also reported in a placebo-controlled trial on healthy adults that high dose vitamin D supplementation significantly increased the frequency of circulating Tregs [108].