Vitamin D Influences the Activity of Mast Cells in Allergic Manifestations and Potentiates Their Effector Functions against Pathogens

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TL;DR

This narrative review synthesizes evidence that vitamin D modulates mast cell (MC) activity by inhibiting IgE-mediated degranulation and pro-inflammatory mediator release while promoting anti-inflammatory IL-10 production. Vitamin D also enhances MC antimicrobial functions by upregulating cathelicidin and β-defensin 2, and by influencing pattern recognition receptor expression. The clinical significance lies in the potential of vitamin D supplementation to stabilize MCs in allergic disorders and bolster host defense against viral and bacterial pathogens.

Full summary

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**Background:** Vitamin D is a fat-soluble secosteroid with established roles in calcium homeostasis and bone health, but its immunomodulatory effects have gained increasing attention. The vitamin D receptor (VDR) is expressed on immune cells including neutrophils, macrophages, activated T and B cells, innate lymphoid cells, and mast cells (MCs). MCs are pro-inflammatory effector cells derived from hematopoietic stem cells that reside in peripheral tissues such as skin, respiratory mucosa, and gastrointestinal tract. They are critically involved in IgE-dependent allergic reactions (anaphylaxis, allergic rhinitis, atopic dermatitis, allergic asthma) and also contribute to host defense against bacteria, fungi, parasites, and viruses. This review aims to compile recent findings on how vitamin D influences MC activity in allergic manifestations and potentiates their effector functions against pathogens.

**Methods:** This is a narrative review that synthesizes published literature on vitamin D, MCs, and their interactions in allergic diseases and infectious diseases. The authors discuss in vitro studies, animal models, and clinical observations. Key experimental approaches include exposure of bone marrow-derived cultured MCs (BMCMCs) to 1α,25(OH)2D3 (calcitriol) followed by IgE + antigen stimulation, and studies of MC behavior in vitamin D-deficient versus sufficient environments. The review also covers studies on antimicrobial peptide induction, pattern recognition receptor (PRR) expression, and cytokine regulation.

**Key Results:** 1. **Inhibition of IgE-mediated MC activation:** Yip et al. demonstrated that calcitriol suppresses IgE-induced MC-derived pro-inflammatory and vasodilatory mediator production in a VDR-dependent manner. BMCMCs exposed to 1α,25(OH)2D3 for 24 hours following IgE + antigen activation showed reduced histamine release, cysteinyl leukotriene, TNF, and IL-6 production. Liu et al. reported that MCs are spontaneously activated in a vitamin D-deficient environment, while vitamin D inhibits IgE-sensitized MC activation by suppressing signaling pathways involving Src family kinase Lyn, spleen tyrosine kinase (Syk), MAPK, and NF-κB, and reducing TNF-α transcription. 2. **MC stabilization:** Vitamin D is essential for maintaining MC stability in both quiescent and sensitized states. In allergic disorders, 1,25(OH)2D3 suppresses Th2 polarization and reduces IL-4 levels in bronchoalveolar lavage fluid in asthma models. In chronic spontaneous urticaria (CSU), vitamin D therapy inhibits the PI3K/Akt/p38 MAPK/HIF-1 signaling cascade, reducing VEGF expression in MCs. 3. **Anti-inflammatory cytokine induction:** Biggs et al. showed that 1,25(OH)2D3 upregulates IL-10 mRNA and induces IL-10 secretion in cutaneous MCs via VDR, without causing degranulation, thereby reducing skin inflammation from chronic UVB exposure. 4. **Antimicrobial peptide induction:** Vitamin D induces expression of cathelicidin (CAMP/LL-37) and β-defensin 2 (DEFB4/HBD2) in immune cells. LL-37 and hBD-2 activate MCs via Mas-related gene X2 (Mrg-x2) and enhance TLR2, TLR4, TLR9, NOD1, NOD2, and RIG-I expression, promoting pro-inflammatory and migratory responses. 5. **Antiviral effects:** Vitamin D has direct antiviral effects against enveloped viruses (SARS-CoV-2, influenza, HIV, EBV, HCV). It modulates TLR activity, reduces TLR2 and TLR4 expression in monocytes (Choi et al. in a Behçet's disease model), and enhances NK cell activity. In dengue virus (DENV) infection, MCs recruit NK cells via CXCL12 and CX3CL1. In respiratory syncytial virus (RSV), MCs produce CCL4, CCL5, CXCL10, and type I/III IFNs, recruiting NKT cells, T cells, and monocytes. Vitamin D also promotes a shift from pro-inflammatory Th1/Th17 to anti-inflammatory Th2/Treg profiles. 6. **Controversies:** Some studies show no association between vitamin D levels and outcomes in hepatitis B/C, influenza, rhinovirus, or HIV infections. For example, Berkan-Kawińska et al. found no evidence that vitamin D deficiency leads to worse prognosis in chronic hepatitis B/C. Similarly, some trials found no effect of vitamin D supplementation on HIV viral loads or mortality.

**Clinical Implications:** The review highlights that vitamin D plays a crucial role in maintaining MC stability and suppressing IgE-mediated allergic inflammation. Vitamin D deficiency may predispose individuals to allergic diseases (asthma, eczema, urticaria) and increase susceptibility to viral infections (COVID-19, influenza, DENV). Vitamin D supplementation or VDR agonists could be potential therapeutic strategies for allergic disorders and infectious diseases by stabilizing MCs, reducing excessive inflammation, and enhancing antimicrobial peptide production. However, the authors note that the precise mechanisms remain to be fully elucidated, and further research is needed to clarify the controversial findings in some viral infections.