Editorial: The Role of Vitamin D as an Immunomodulator – Volume II

Mourad Aribi^1*Franck JD Mennechet²Chafia Touil-Boukoffa¹

• ¹Laboratory of Applied Molecular Biology and Immunology, University of Abou Bekr Belkaïd, Tlemcen, Algeria
• ²INSERM U1058, University of Montpellier, Montpellier, France

Vitamin D has emerged as a multifaceted molecule, acting not only as a regulator of metabolic and skeletal homeostasis but also as a modulator of immune responses (1)(2)(3). This dual functionality underscores the need to clarify the conceptual distinction between regulation and modulation, particularly within the framework of immunology. The following sections provide an integrated overview of the conceptual principles, molecular foundations, immunomodulatory mechanisms, and systemic relevance of vitamin D as a key homeostatic factor. Vitamin D continues to emerge as a pleiotropic regulator of immune and metabolic homeostasis, operating at the crossroads of endocrine, skeletal, and immune systems (4)(5)(6). Traditionally recognized for its role in calcium-phosphate balance and bone mineralization, vitamin Dfunctioning both as a vitamin and a pre-hormone-exerts wide-ranging biological effects through its active metabolite, 1,25-dihydroxyvitamin D₃ [1,25(OH)2D3] (7)(8)(9)(10). This metabolite binds to the vitamin D receptor (VDR), a ligand-dependent nuclear transcription factor expressed in numerous immune and non-immune cells, including those in the intestine, pancreas, bone, and skin (11). Upon activation, the 1,25(OH)2D3-VDR complex forms a heterodimer with the retinoid X receptor (RXR-α) and binds to vitamin D response elements (VDREs) in target genes, thereby regulating transcriptional programs involved in cell proliferation, differentiation, cytokine secretion, and immune tolerance (12)(13)(14)(15).Physiologically, vitamin D is synthesized in the skin from 7-dehydrocholesterol upon exposure to ultraviolet B radiation (290-320 nm) and subsequently hydroxylated in the liver and kidney by CYP2R1 and CYP27B1 to generate its active form (16,17). The expression of these metabolic enzymes and the VDR within immune and non-immune tissues underscores the body's intrinsic capacity to locally produce and respond to calcitriol, thereby modulating both autocrine and paracrine signaling networks. Beyond its classical skeletal actions, vitamin D plays critical roles in neuromuscular function and in regulating key cellular processes such as growth, differentiation, apoptosis, and glucose metabolism (18)(19)(20)(21)(22)(23)(24)(25). Collectively, these multidimensional effects position vitamin D as a central integrator of immune regulation, metabolic balance, and overall systemic health. In immunology, the terms immunomodulation and immune regulation are often used interchangeably, yet they represent distinct biological concepts.Immune regulation refers to the intrinsic, homeostatic mechanisms by which the immune system maintains balance between activation and tolerance (26)(27)(28). These include key processes such as central and peripheral tolerance, the action of regulatory immune cells, cytokine feedback loops, and the suppression of excessive or self-reactive immune responses (29)(30)(31). In essence, immune regulation ensures the preservation of immune equilibrium and self-tolerance under physiological conditions. By contrast, immunomodulation encompasses any external or endogenous intervention-pharmacological, nutritional, hormonal, or microbial-that alters immune activity, either by enhancing or suppressing or redirecting specific cellular functions (32)(33)(34). Immunomodulators can therefore act as stimulants, suppressants, or balancing agents depending on the immunological context (Figure 1). Through interconnected pathways, vitamin D acts as a pivotal modulator of both innate and adaptive immunity. It strengthens antimicrobial defenses by inducing the expression of potent effector peptides, including cathelicidin and β-defensin 2, while simultaneously attenuating excessive inflammation by downregulating proinflammatory mediators (35)(36)(37). By fine-tuning cytokine networks and antigen-driven responses, vitamin D maintains a delicate equilibrium between immune activation and tolerance, promoting resolution of inflammation and preserving tissue integrity and homeostasis. Vitamin D thus exemplifies a potent immunomodulatory agent, as it influences both regulatory and effector immune mechanisms (38). It does not merely suppress or activate immune functions, but rather modulates their intensity and quality, promoting an adaptive state of functional equilibrium that is essential for immune homeostasis. In this regard, vitamin D serves as a paradigm of context-dependent immunomodulation (39)-a molecular sentinel that operates through finely regulated receptormediated signaling to maintain immune homeostasis. The compelling body of work compiled here, comprising 14 original research and review articles, highlights the growing interest of vitamin D and significantly advances our understanding of its immunomodulatory effects across a broad spectrum of conditions-from allergic and autoimmune diseases to viral infections like COVID-19, pregnancy-related disorders, inflammatory bowel diseases, metabolic syndromes, and cancer. This editorial synthesizes the key contributions of this volume, emphasizing the convergence of mechanistic insights and clinical applications. In obstetric immuno-hematology, the clinical study by Wang et al. shows that gestational hypertension is associated with lower vitamin D levels and platelet counts (PLT), along with higher mean platelet volume (MPV), platelet distribution width (PDW), and D-dimer levels.Vitamin D was significantly correlated with these parameters, suggesting a potential role in modulating platelet function and coagulation, and highlighting the value of optimizing vitamin D status in managing this condition. The demonstrate that vitamin D deficiency or insufficiency is associated with more severe acute disease, prolonged hospitalization, and a 2.2-fold higher risk of long COVID-particularly with neurological and musculoskeletal symptoms-underscoring the importance of age-specific preventive approaches. Population and clinical cohort studies add epidemiological weight to mechanistic findings. Liu et al. report that lower serum 25(OH)D is associated with a higher incidence of hyperlipidemia in adults, highlighting the link between lifestyle-related vitamin D insufficiency and adverse lipid profiles. In the inflammatory bowel disease field, Zheng et al. report that higher baseline vitamin D levels independently predict clinical remission in infliximab-treated Crohn's disease patients, suggesting that vitamin D status may influence biologic therapy outcomes and patient stratification. In their Opinion article, Su et al. revisit the debated field of high-dose vitamin D supplementation as a potential approach to immune recalibration in autoimmune diseases, highlighting its capacity to modulate Th1, Th17, and regulatory T-cells, alongside B-cell activity, in selected conditions, including multiple sclerosis, systemic lupus erythematosus, and Crohn's disease. Adding a genetic perspective, Huang et al. applied a Mendelian randomization framework leveraging genetic variants linked to various circulating micronutrients, including vitamin D, to dissect causal relationships with systemic lupus erythematosus (SLE). Using summary statistics from the IEU OpenGWAS database and supported by multiple sensitivity analyses (including MR-PRESSO, MR-Egger, and leave-one-out), their findings provide genetic evidence for a protective role of selected nutrients-notably vitamin D and calciumagainst autoimmune susceptibility, highlighting the value of integrative nutrigenomic approaches.