Molecular Insight into the Role of Vitamin D in Immune-Mediated Inflammatory Diseases

Abstract

In the last decades, it has become increasingly evident that the role of vitamin D extends beyond the regulation of calcium homeostasis and the maintenance of bone health. A significant extraskeletal function of vitamin D is its role in modulating the immune system, particularly highlighted in the context of immune-mediated inflammatory diseases, where correlations between vitamin D status and genetic variations in the vitamin D receptor have been observed about the incidence and severity of these conditions. Additionally, different studies have reported the existence of immunomodulatory effects of vitamin D, particularly the effects of vitamin D on dendritic cell function, maturation, cytokine production, and antigen presentation, and that its deficiency may be associated with a sub-inflammatory state. In this sense, different clinical trials have been conducted to assess the therapeutic efficacy of vitamin D in different immune-mediated inflammatory disorders, including asthma, atopic dermatitis (AD), rheumatoid arthritis (RA), psoriasis, thyroid diseases, infectious diseases, and systemic lupus erythematosus (SLE). This review will provide a comprehensive overview of the current understanding of the molecular mechanisms underlying vitamin D's immunomodulatory properties, its role, and innovative therapeutic applications in patients with immune-mediated inflammatory diseases.

Keywords: adaptive immunity; asthma; atopic dermatitis; immune-mediated inflammatory disorders; infectious diseases; innate immunity; psoriasis; rheumatoid arthritis; systemic lupus erythematosus; thyroid diseases.

Figure 1

The immune-mediated and anti-inflammatory actions of vitamin D from bench to bedside.

Figure 2

Synthesis and mechanism of action of vitamin D on bone metabolism and, in particular, on innate and adaptive immunity cells. Transcription factors FOXP3 (Forkhead box P3), GATA3, TBX21 (T-bet), RUNX1, RORγt, and NF-kb (protein complex functioning as a transcription factor) with its isoform p65. P35 and P40 are subunits of IL-12. VDRE is a type of DNA sequence found in the promoter region of vitamin D-regulated genes.

Figure 3

Mechanism of action of vitamin D on monocytes and macrophages. TLRs expressed on monocytes’ and macrophages’ surfaces recognize components of bacteria, fungi, and viruses, upregulating the expression of VDR and CYP27B1. CYP27B1 metabolizes 25-hydroxyvitamin D into calcitriol and binds to VDR. The activated VDR forms a heterodimer with RXR, which induces the synthesis of cathelicidin, β-defensin 2 that promotes bacterial and viral autophagy. 25(OH)D: 25-hydroxyvitamin D; 1,25(OH)2D: 1-25-Dihydroxyvitamin D, NF-kb: Nuclear Factor Kappa light chain-enhancer of activated B cells; IL-1R: interleukin-1 receptor; NOD2: Nucleotide-binding oligomerization domain-containing protein 2; TLR: Toll-Like Receptor; VDR: vitamin D receptor.

Figure 4

Mechanism of action of vitamin D on dendritic cells and lymphocytes. In particular, calcitriol promotes the expression of the anti-inflammatory cytokine IL-10, and it suppresses IL-12 production, which determines the differentiation of T helper cells into Th1 cells. Conversely, the anti-inflammatory cytokine IL-10 promotes the differentiation of regulatory T cells. Moreover, calcitriol promotes Th2-type differentiation and the secretion of IL-4, IL-5, and IL-10, anti-inflammatory cytokines. 1,25(OH)2D: 1-25-Dihydroxyvitamin D; IL-2: interLeukin-12; IL-10: interLeukin-10; Th1: T Helper 1 lymphocytes; Th2: T Helper 2 lymphocytes; T reg: T regulatory cells; TGF-β: transforming growth factor beta; TNF-α: Tumor Necrosis Factor alpha.