Genomic or Non-Genomic? A Question about the Pleiotropic Roles of Vitamin D in Inflammatory-Based Diseases

Abstract

Vitamin D (vit D) is widely known for its role in calcium metabolism and its importance for the bone system. However, various studies have revealed a myriad of extra-skeletal functions, including cell differentiation and proliferation, antibacterial, antioxidant, immunomodulatory, and anti-inflammatory properties in various cells and tissues. Vit D mediates its function via regulation of gene expression by binding to its receptor (VDR) which is expressed in almost all cells within the body. This review summarizes the pleiotropic effects of vit D, emphasizing its anti-inflammatory effect on different organ systems. It also provides a comprehensive overview of the genetic and epigenetic effects of vit D and VDR on the expression of genes pertaining to immunity and anti-inflammation. We speculate that in the context of inflammation, vit D and its receptor VDR might fulfill their roles as gene regulators through not only direct gene regulation but also through epigenetic mechanisms.

Full text

Citation: Holick, M.F.; Mazzei, L.;
García Menéndez, S.; Martín
Giménez, V.M.; Al Anouti, F.;
Manucha, W. Genomic or
Non-Genomic? A Question about the
Pleiotropic Roles of Vitamin D in
Inflammatory-Based Diseases.
Nutrients 2023,15, 767. https://
doi.org/10.3390/nu15030767
Academic Editor: Carsten Carlberg
Received: 6 December 2022
Revised: 10 January 2023
Accepted: 18 January 2023
Published: 2 February 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
nutrients
Review
Genomic or Non-Genomic? A Question about the Pleiotropic
Roles of Vitamin D in Inflammatory-Based Diseases
Michael F. Holick 1,* , Luciana Mazzei 2,3, Sebastián García Menéndez 2,3 , Virna Margarita Martín Giménez 4,
Fatme Al Anouti 5and Walter Manucha 3,6,*
1Section on Endocrinology, Diabetes, Nutrition & Weight Management, Department of Medicine, School of
Medicine, Boston University, Boston, MA 02118, USA
2Instituto de Bioquímica y Biotecnología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo,
Mendoza 5500, Argentina
3Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones
Científicas y Tecnológicas (CONICET), Mendoza 5500, Argentina
4Instituto de Investigaciones en Ciencias Químicas, Facultad de Ciencias Químicas y Tecnológicas,
Universidad Católica de Cuyo, San Juan 5400, Argentina
5Department of Health Sciences, Zayed University, Abu Dhabi P.O. Box 144534, United Arab Emirates
6Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de
Cuyo, Mendoza 5500, Argentina
*Correspondence: mfholick@bu.edu (M.F.H.); wmanucha@fcm.uncu.edu.ar (W.M.);
Tel.: +54-261-4494116 (W.M.)
Abstract:
Vitamin D (vit D) is widely known for its role in calcium metabolism and its importance
for the bone system. However, various studies have revealed a myriad of extra-skeletal functions,
including cell differentiation and proliferation, antibacterial, antioxidant, immunomodulatory, and
anti-inflammatory properties in various cells and tissues. Vit D mediates its function via regulation of
gene expression by binding to its receptor (VDR) which is expressed in almost all cells within the body.
This review summarizes the pleiotropic effects of vit D, emphasizing its anti-inflammatory effect on
different organ systems. It also provides a comprehensive overview of the genetic and epigenetic
effects of vit D and VDR on the expression of genes pertaining to immunity and anti-inflammation.
We speculate that in the context of inflammation, vit D and its receptor VDR might fulfill their roles
as gene regulators through not only direct gene regulation but also through epigenetic mechanisms.
Keywords: vitamin D; genetic; genomic; epigenetic; immunity; inflammation
1. Introduction
Vitamin D (vit D) is a fat-soluble vitamin that can be found in two different chemical
structures: cholecalciferol (vit D3) or ergocalciferol (vit D2) [
1
]. The exposure to ultraviolet
B rays, present in sunlight, is the most effective natural source of vit D. It also can be
obtained by the consumption of some fatty fish (tuna, salmon, and mackerel), sun-exposed
mushrooms, beef liver, cheese, egg yolks, fortified foods, or even by supplements [2].
The active form of the vit D (D represents either and/or vitamin D2 and vitamin D3)
is 1,25-dihydroxyvitamin D (1,25(OH)2D) To become 1,25(OH)2D, first vit D is transported
to the liver, where it is modified to 25-hydroxyvitamin D (25(OH)D) by CYP2R1, which
is a 25-hydroxylase enzyme. Later, in the kidneys, 25(OH)D undergoes an additional
hydroxylation by the enzyme 25 hydroxyvitamin D-1
α
-hydroxylase (CYP27B1), converting
it to 1,25(OH)2D [3,4].
There is a lot of controversy about the optimal levels of 25(OH)D which is the measure
of a person’s vitamin D status [
5
]. Most agreements indicate vit D deficiency is defined
at values below 20 ng/mL, insufficiency between 21–29 ng/mL and sufficiency at values
> 30 ng/mL, with the range between 40–60 ng/mL being preferred, and vit D intoxication
at values above 150 ng/mL as recommended by the Endocrine Society Practice Guidelines
Nutrients 2023,15, 767. https://doi.org/10.3390/nu15030767 https://www.mdpi.com/journal/nutrients

Nutrients 2023,15, 767 2 of 13
on Vitamin D [
6
]. However, according to the Institute of Medicine (IOM), for the majority of
the population, a minimum 25(OH)D serum level of 20 ng/mL (50 nmol/L) is considered
adequate with limited sun exposure. Meanwhile, the risk of vit D deficiency is considered
significant when the 25(OH)D serum concentrations are below 12 ng/mL (30 nmol/L) [
7
].
Such thresholds of serum 25(OH)D concentrations were established for maximum bone
health and higher thresholds have been recommended for optimal overall health because of
the strong association between vit D deficiency and cardiovascular diseases, certain types
of cancer, type 2 diabetes mellitus, hypertension, metabolic syndrome, infectious diseases,
autism, depression, autoimmune diseases, and others [8].
In this context, given that the inflammatory process is directly or indirectly involved
in the main underlying mechanisms of most of the pathologies affecting current societies
(such as those previously mentioned), the present review aims to summarize the pleiotropic
effects of vit D, emphasizing its anti-inflammatory impact on different organ systems.
Likewise, this review aims to provide a comprehensive overview of the genomic and
non-genomic effects of vit D and vit D receptor (VDR) related to immunity and anti-
inflammation. Deepening this knowledge would help develop new therapeutic alternatives
for many diseases that constitute important causes of morbidity and mortality worldwide.
2. Pleiotropic Effects of Vitamin D in Inflammatory-Based Diseases
Numerous pleiotropic effects have been reported for vit D since its discovery a century
ago. Today it is well known that in addition to its pivotal role in calcium homeostasis
and bone metabolism, vit D has antibacterial, anti-proliferative, immunomodulatory, and
anti-inflammatory actions, among other beneficial properties [9,10].
The nuclear VDR mediates two types of actions of 1,25(OH)2D:
-Non-genomic pathway: Ligand binding to the cytosolic population of VDRs trig-
gers multiple intracellular signaling pathways or cascades, leading to immediate gene
transcription-independent responses in cells. These pathways may also contribute to
ultimately modulating the expression of target genes in the nucleus [2].
-Genomic pathway: The retinoic acid receptor (RXR) forms a heterodimer with the
VDR bound to 1,25(OH)2D. The heterodimer translocates to the cell nucleus and binds to
the vit D response element (VDRE) in the promoter regions of target genes, consequently
regulating nuclear transcription. The binding of the ligand to VDR modifies the conforma-
tion of its LBD region, usually promoting the release of transcriptional co-repressors and the
recruitment of co-activators and enzymes (histone acetylases) that modify the structure of
chromatin, facilitating the transcriptional activation of genes. In other cases, the effect could
be transcriptional repression; however, the exact mechanisms of such down-regulation are
not well known [2].
VDR is expressed in the skin, parathyroid glands, adipocytes, small intestine, colon,
and in other tissues [
11
,
12
]. Moreover, the VDRE is found in numerous genes, explaining
the mechanisms associated with vit D, such as immune functions, intestinal barrier function,
cell proliferation, gut microbiota modulation, and autophagy. Vit D immunomodulatory
effects particularly have been widely investigated by several researchers [
13
–
15
]. Such
effects were attributed to a direct relation to antigen-presenting cells and T-cells functions.
Moreover, the lack of 1,25(OH)2D harms regulatory T-cells differentiation and weakens its
functions, which may trigger autoimmune diseases [16,17].
In addition to its important anti-inflammatory role, vit D can exert protective effects against
reactive oxygen species (ROS) and nitric oxide and may prevent oxidative damages [
10
]. It
also reduces glutathione (GSH) synthesis, which is essential to glutathione peroxidase (GPX)
activity, through the regulation of the gamma-glutamyl transpeptidase (g-GT) expression. Vit
D cans also increase GSH formation by increasing glucose-6-phosphate dehydrogenase (G6PD),
glutamate-cysteine ligase (CGL), and glutathione reductase activity [18].
Furthermore, vit D plays a role in antioxidants synthesis by regulating Klotho and
Nrf2 (Nuclear factor erythroid 2–related factor 2) expression, both of which are essential to
ROS signaling pathway function [19].

Nutrients 2023,15, 767 3 of 13
Vit D is involved in the regulation of muscle development and contractility through
genomic actions, and stimulating the proliferation of muscle cells and their differentiation
through the transcription of genes that express an increase in cellular DNA synthesis, followed
by the induction of muscle proteins, specifically calcium and myosin binding proteins [
20
].
Vit D also exerts non-genomic actions by interacting with the specific muscle cell membrane
receptor, which leads to the stimulation of adenyl cyclase and phospholipases C, D, and A2,
and the activation of intracellular signaling pathways, such as MAPK (Mitogen-activated
protein kinase) cascade, ultimately enhancing cell division [
21
]. In a recently published study
by Max et al. [
22
], the authors observed that mice born from mothers with vit D deficiency had
smaller muscle cells than mice whose mothers had adequate levels. It has long been observed
that vit D deficiency leads to a myopathy characterized by proximal muscle weakness and
atrophy, and the presence of VDR in skeletal muscle tissue has been supported by several
studies which documented a decline in receptors with age [23].
2.1. The Role of Vitamin D in Inflammation at the Cardiovascular Level
Vit D deficiency is associated with an increase in serum levels of pro-inflammatory me-
diators, including IL-6 and tumor necrosis factor-alpha (TNF-
α
), which are related to both
the development and progression of some vascular inflammatory pathologies [
14
,
15
,
24
,
25
].
In addition, a study carried out on obese patients revealed that reduced serum 25(OH)D
concentrations were usually related to increased levels of other biomarkers of vascular
inflammation such as high-sensitivity C reactive protein (hCRP) and fibrinogen [
26
]. Sim-
ilar conclusions were informed for severely obese children [
27
,
28
]. The 25(OH)D levels
below 20 ng/mL were associated with increased markers of oxidative/nitrosative stress,
inflammation and endothelial activation, all of them indicators of cardiovascular risk.
Moreover, in obese people, hyperleptidemia is usually observed. This disorder provokes
vascular inflammation [
29
]. The 1,25(OH)2D3 pretreatment of cultured human umbilical
vein-derived endothelial cells exposed to high concentrations of leptin with 1,25(OH)2D3
prevented the rise in the expression of vascular pro-inflammatory mediators caused by
leptin, including CCL2, VCAM-1, and transforming growth factor
β
(TGF-
β
) [
30
]. Further-
more, Oma et al. [
31
] observed a higher presence of mononuclear cell infiltrates in the aortic
adventitia of patients with coronary artery disease and vit D deficiency as compared with
those with suiTable 25(OH)D levels. The adhesion of monocytes to endothelial cells repre-
sents an early stage in atherosclerosis development, thus, vit D supplementation would be
a helpful tool in the prevention and treatment of atherosclerosis and other vascular inflam-
matory diseases [
32
]. Furthermore, it has also been suggested that vit D deficiency and the
down-regulation of its receptor could be involved in aggravating vascular inflammation
in pregnant women during preeclampsia (pregnancy hypertension). Interestingly, vit D
supplementation reversed the inflammatory process in these patients [
33
]. These findings
along with the significant number of VDR located in vascular smooth muscle cells (VSMCs)
and endothelial cells indicates a crucial role of this endogenous compound in the regulation
of inflammation, especially at the vascular level [34].
The location of VDR in VSMCs is of particular interest since these cells represent
the majority of cell population in the blood vessel walls’ levels and they have a vital role
in the advance of vascular inflammatory disease. New technologies have shown that
VSMCs may switch their contractile phenotype to a macrophage-like phenotype, proving
the plasticity of these cells. Thus, there is interplay among VSMCs, immune cells, and
endothelial cells during the convoluted process of vascular inflammation where VSMCs
can control, interact with, and influence the behavior of other cellular components of
the blood vessel wall [
35
]. In this context, a study carried out using an
in vitro
model
of endothelial inflammation (primary cultured human umbilical vein endothelial cells
exposed to TNF-
α
) showed that the treatment with paricalcitol (a vit D analog) inhibited
the increased expression of the intercellular adhesion molecule-1 (ICAM-1), vascular cell
adhesion molecule-1 (VCAM-1), and fractalkine (a chemoattractant cytokine) in these
cells [
36
]. Furthermore, in a clinical model of vascular inflammation (patients with an

Nutrients 2023,15, 767 4 of 13
abdominal aneurysm), paricalcitol reduced the CD4+ T-helper and the T-cell (CD3+) content
in aneurysm wall samples from these patients. Paricalcitol also prevented the rise in the
levels of pro-inflammatory cytokines (IL-1
β
, IL-6, IL-8, and TNF-
α
) in cultured human
aortic smooth muscle cells exposed to elevated concentrations of phosphate, indicating that
active vit D derivatives have anti-inflammatory effects at the vascular level [37].
Likewise, VDRs also modulate the RAAS, inflammation, and fibrosis. Thus, their
activation counteracts myocardial hypertrophy and hypertension [
38
]. In this regard, it
is proposed that the activation of VDRs associated with Hsp70 (as a chaperone protein)
could favor physiological cardiac remodeling after a myocardial infarction and reduce
progression to heart failure [39].
In SHR rats, treatment with vit D analogs ameliorates left ventricular hypertrophy and
improves left ventricular diastolic measures. Mizobuchi et al. [
40
] showed that combined
therapy with enalapril and paricalcitol significantly decreased proteinuria, glomerulo-
sclerotic index, and tubulointerstitial volume in uremic rats [41].
In addition, experimental studies suggest that active vit D analogues at low doses
ameliorate myocardial renin overexpression and lower blood pressure, protect against
aortic calcification and prevent cardiac/vascular remodeling [42].
Moreover, our previous work [
38
] in rats with a ureteral obstruction showed a re-
duction in myocardial VDR expression, and this fact, might be related to myocardial
remodeling associated with an increase in arrhythmogenesis. Important to note, that
paricalcitol protects against these changes by restoring myocardial VDR levels [38].
For its part, vit D deficiency at the cellular level produces a higher oxidative stress,
inflammatory markers, and mitochondrial damage. Serum 25(OH)D concentrations below
25 ng/mL were related to an increase in vascular tone mediated by smooth muscle contraction,
either through direct effects on vascular smooth muscle cells, up-regulation of the RAAS,
and/or through modulation of calcium metabolism with secondary hyperparathyroidism;
which predisposes patients to develop hypertrophy of the left ventricle and of the vascular wall,
causing hypertension. The VDR plays a role at the mitochondrial level and the regulation
of the respiratory chain, which would influence arterial remodeling, since its activation
would reduce oxidative damage and preserve cell life. Such data implicates that maintaining
adequate levels of vit D is important for protection against cardiovascular disease [42].
Several studies assessed the effect of calcitriol administration as an anti-inflammatory
agent. On an apoE (
−
/
−
) mouse model of abdominal aneurysm induced by angiotensin-II
(Ang-II) infusion, the oral treatment with calcitriol reduced the aneurysm formation and
all altered parameters observed during abdominal aneurysm were decreased, including
macrophages infiltration, expression of vascular endothelial growth factor (VEGF), angio-
genesis, monocyte chemoattractant protein 1 (CCL2), CCL5, and CXCL1 chemokines and
synthesis of matrix metalloproteinase-2 and 9 (MMP-2 and 9) [
43
]. In an
in vitro
model of
human endothelial cells, the treatment caused inhibition of leukocyte-endothelial cell inter-
actions induced by Ang-II, morphogenesis, and synthesis of endothelial pro-inflammatory
and angiogenic chemokines mediated by VDRs [43,44].
In addition, vit D administration decreases the expression of pro-inflammatory and
proatherogenic cytokines such as IL-2 and interferon-gamma (IFN-
7
), which are responsible
for the T-helper-1 cells activation and vascular inflammation [
45
]. Accordingly, clinical
studies showed that vit D supplementation was able to reduce central blood pressure
parameters in individuals with vit D deficiency, but not in individuals with adequate
vit D status. It was also reported to improve arterial stiffness in overweight African
Americans patients with vit D deficiency and to improve microvascular responses in African
Americans, mitigating or preventing the development of cardiovascular dysfunction in this
population [46].
2.2. Anti-Inflammatory Role of Vitamin D in the Gastrointestinal System
Vit D helps the intestine absorb calcium and phosphate and its deficiency is correlated
with increased mucosal inflammation, leading to inflammatory bowel disease (IBD) [
2
].

Nutrients 2023,15, 767 5 of 13
However, administration of the vit D at a dose that raises and maintains a 25(OH)D of
30 ng/mL, may have the ability to reduce the disease. Moreover, VDR has been linked
to the gut microbiota and its metabolites and its expression is down-regulated in Crohn’s
disease (CD) and ulcerative colitis [2].
VDR is regulated by miRNAs, which are a class of small non-coding RNA (17–22 nu-
cleotides) that regulates gene expression post-transcriptionally. It also inhibits transcription
of ZO-1, claudin-5, and occludin genes and increases the tight junction protein claudin-2
which enhance intestinal permeability. Thus, lacking intestinal epithelial VDR regulation in
inflamed intestine leads to hyperfunction of Claudin-2 and exaggerates the inflammatory
responses in the intestines [47].
2.3. Vitamin D Role in Renal Protection
Several animal models have suggested a role for active vit D in albuminuria and
kidney fibrosis. In fact, vit D analogues are able to affect blood pressure, proteinuria, and
inflammation. A study carried out on VDR knockout mice reveals a rise in renin consequent
to loss of normal suppression of the renin-angiotensin aldosterone system (RAAS) by vit
D [
48
]. Thus, RAAS have been shown to play an important role in the progression of
chronic kidney disease (CKD) and low levels of 25(OH)D and 1,25 (OH)2D were correlated
to be predictors of disease progression and death in patients with CKD and End Stage
Renal Disease [49].
In this regard, in previous investigations, the expression of VDR and genes associated
with nephrogenesis in spontaneous hypertension rats (SHR) from week 0 to 8 of life were
analyzed. Hypertension in these rats is known to develop at about 6 weeks of age [
50
]. We
observed a decrease in the expression of the nephrogenic gene, wt-1, and VDR by week
4, before the establishment of arterial hypertension, suggesting that the alteration in the
kidney occurs previous to the increase in blood pressure [51].
Moreover, our group has found in adult SHR rats that the induction of VDR modulates
an increase in Hsp70 levels, with a decrease in the angiotensin II receptor, type 1 (AT1)
expression, providing renal protection [
41
]. Of interest, Hsp70 effects on the VDR may also
accentuate repressive anti-inflammatory signaling [52].
2.4. The Role of Vitamin D in the Nervous System
As early as the early 1980s, attempts were made to find a relationship between the
nervous system and vit D, starting with the question of whether vit D was able to cross the
blood-brain barrier [
53
]. Today the questions revolve around the relationship of vit D status
and its interaction with antioxidant mechanisms, complex immunomodulatory systems,
and neurotrophic factors among others [
19
,
54
]. As a result, vit D has a key part in the
process of neuro-inflammation, cognitive decline, and neurodegeneration [
55
]. In line with
this, it has recently been reported that vit D has a neuroprotective function in aging cognitive
decline [
56
]. This is one of the reasons why many human dietary supplements include vit D
alone or in combination with other compounds that have antioxidant effects. A closer look
into the different cell types of the nervous system, VDR are found in neurons, astrocytes, and
microglia in the central nervous system [
54
]. Furthermore, using the 25-hydroxyvitamin
D-1alpha-hydroxylase (CYP27B1) and 25-hydroxyvitamin D-24-hydroxylase (CYP24A1)
enzymes, some of these cells may synthesize and catabolize 1,25(OH)2D. The unequal
distribution of 1,25(OH)2D and 25(OH) D in different parts of the brain shows that vit D and
its metabolism in the CNS might either function in a paracrine or autocrine manner [57].
Many studies have discovered that appropriate amounts of vit D reduce oxidative
stress and brain inflammation, resulting in diverse neuroprotective benefits [
58
]. The VDR
is also implicated in the neuroprotective effects of neurosteroids. Furthermore, calcitriol has
been shown to stimulate VDR expression, down-regulate NOX2, and inhibit cellular death
rate [
59
], suggesting that VDR-activated ERK1/2 activation may contribute to neuronal
apoptosis prevention [
60
]. On the other hand, findings show that vit D shortage causes

Nutrients 2023,15, 767 6 of 13
significant changes in microglia, implying that these cells may play a role in the sensory
dysfunctions associated with hypovitaminosis D [61].
The human brain produces 1,25(OH)2D3, which affects a variety of brain areas, in-
cluding the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and
substantia nigra. The 1,25(OH)2D3 lowers oxidative stress, inhibits inflammation, offers
neuroprotection, down-regulates inflammatory mediators, and up-regulates neurotrophins
in neurons [62].
The Klotho gene, which was initially discovered as an ‘aging suppressor’ in mice,
encodes the antiaging protein Klotho. Klotho deficiency is linked to early mortality and
rapid aging, but its overexpression is linked to longevity. Klotho protein is involved in the
control of a number of biological processes, including calcium-phosphate balance, PTH,
and vit D metabolism [
63
]. The precise chemical pathways through which 1,25(OH)2D3 and
Klotho protein exerts its activities in the brain are yet unknown; however, the relationship
between them might be both genomic and non-genomic, but the interplay processes are
mainly unknown [63].
For all the above reasons, we could hypothesize that the therapeutic use of 1,25(OH)2D3
or similar agonists may have considerable promise due to its documented function in neu-
roinflammation, neurodegenerative diseases, and neuropsychiatric disorders.
Depression is a frequent mental illness in the elderly that lowers quality of life and
increases morbidity and death. Vit D may play a role in the onset and treatment of
depression as a neuro-steroid hormone [
64
]. One of the proposed mechanisms by which
this neurohormone exerts its action is its relationship with serotonin and dopamine levels
in the brain [65].
2.5. The Role of Vitamin D in Autoimmunity
Clinical studies have suggested that VDR polymorphisms and vit D deficiency is related
to the development and progression of several autoimmune diseases, such as rheumatoid
arthritis, systemic lupus erythematosus, multiple sclerosis, and autoimmune endocrine dis-
orders (e.g., Hashimoto thyroiditis, type-1 diabetes mellitus (T1DM), Addison’s disease,
and Graves’ disease) [
66
]. As mentioned, due to its great ability to bind to VDR and act
as a transcriptional factor, vit D may modulate gene expression and, consequently, exert
immunomodulatory effects on immune cells. Vit D has the capability to inhibit the produc-
tion of Th17 cytokine, improve Treg activity, stimulate NKT cell functions, inhibit Th1, and
induce the production of Th2 cytokine, and thereby shift T cells toward Th2 profile [
67
].
However, the role of vit D supplementation in the improvement of autoimmune diseases
remains unclear. Therefore, additional studies are needed to know the potential underlying
mechanisms involved [
68
]. Of note, all the clinical studies performed so far, only demonstrate
correlations. Thus, it is difficult to establish whether the low 25(OH)D3 level is the cause or
the consequence of autoimmune diseases [
69
]. Despite several studies having demonstrated a
beneficial effect of vit D supplementation in autoimmune diseases, there are also some studies
that did not show any effect on the main parameters of this kind of diseases. This could be
due to differences in the supplementation strategy or the individual characteristics of the
subjects included in the study, which are aspects that should be addressed in a properly way
at the moment of designing multicenter clinical trials [70,71].
3. Genetic and Epigenetic Regulation of Inflammation by Vitamin D
Epigenetics might explain the interplay between environment and genetics in the
development, progression, pathogenicity of disease, and the response to treatments. Epige-
netics changes occur in the following ways: DNA methylation, which generates methyl
cytosine in CpG dinucleotides sites leading to transcriptional silencing, histone modifica-
tions, chromatin remodeling, and noncoding RNAs regulation [
29
]. RNAs are untranslated
transcripts that play an important role in the post-transcriptional regulation of gene ex-
pression and can be classified into short, mid, and long based on their length. Among the
noncoding RNAs, long noncoding RNAs (lncRNAs) regulate gene expression by interacting

Nutrients 2023,15, 767 7 of 13
with DNA, messenger RNAs (mRNAs), and proteins, while microRNAs (miRNAs) mediate
the post-transcriptional repression or mRNA degradation in an epigenetic mechanism [
72
].
One of the most usual processes observed during vascular inflammation is histone
acetylation/deacetylation. Acetylation of histones (by histone acetyltransferases) is the
addition of positively charged acetyl groups to amino acid residues, which neutralizes the
negative charges of DNA reducing the affinity of histones to DNA, and leading to a more
relaxed chromatin state to allow higher accessibility to the transcriptional machinery [
73
].
Likewise, the opposite mechanism (deacetylation of histones) is carried out by histone
deacetylases (HDACs) [
74
]. Of interest, alterations in any of these systems may produce
abnormal activation or silencing of specific genes, which favors vascular disease onset. In
addition, transgenerational transmission of epigenetic signaling is informed to precede
vascular damage in children and young adults [
75
]. Thus, it is needed to investigate
the existing link between epigenetics and inflammation in the vasculature to understand
how epigenetic changes may influence these biological processes and how they could be
managed to inhibit the inflammatory cascade at the vascular level [76].
Notably, during pregnancy, most calcitriol is produced in the maternal kidneys and
a small proportion in the placenta [
77
]. Vit D induces epigenetic changes that modify the
way the placenta responds to this compound and its metabolites and can even reduce the
epigenetic changes associated with gestational aging and also plays a role in modifying
the immune response of the fetus [
78
]. Moreover, this research suggests that maternal
25(OH)D levels influence gene expression profiles, and these changes could contribute to
fetal immune imprinting and reducing allergic sensitization in the first years of life [78].
It is relevant to highlight that pregnant women are at an increased risk of developing vit
D deficiency, and this is associated with adverse health consequences among their offspring,
such as hypertension, hypocalcemia, deficient postnatal growth, and autoimmune diseases,
among others [
79
]. Regarding this, exposure of male and female Sprague-Dawley rats to
a vit D-free diet before mating led to an increase in systolic and diastolic blood pressure
in their offspring, in addition to the hypermethylation of the Pannexin-1 (Panx1), a gene
responsible for endothelial relaxation of large blood vessels [
80
]. Using the same model,
Zhang and coworkers also showed that maternal vitamin D-free diet (and ultraviolet-free
light) during pregnancy may cause insulin resistance in the offspring, which is accompanied
by persistent increased inflammation. The vit D-free diet caused a significant increase in
NFKBIA methylation at the CpG site +331 in the offspring. NFKBIA protein interacts with
REL dimers to block NF-kappa-B/REL complexes which are involved in inflammatory
pathways. Hence, through epigenetic modifications, the persistent lower I
κ
b
α
expression
levels in the progeny stimulates the activation of NF-
κ
B signaling which, in turn, leads
to inflammation with possible implication for the insulin resistance in adulthood [
81
].
These studies emphasize the relevance of vit D supplementation for the prevention of
epigenetically induced vascular inflammatory pathologies.
In fact, there is strong evidence that vit D and epigenetic mechanism programming is
highly related. As previously mentioned, calcitriol acts through its binding to the nuclear-
cytosolic VDR. After the heterodimer VDR-RXR is formed, genomic action is performed via
docking of the VDR-RXR complex to the VDRE in the proximal region of promoter genes
modulated by vitamin D [
82
,
83
]. The level of chromatin accessibility in the VDRE regions is
crucial for VDR target gene transcription. Hence, VDREs cannot be accessed by the active
VDR-RXR complex if it is inside a hypermethylated heterochromatin region. Therefore, the
transcriptional control of VDR-responsive genes is dependent on three mechanisms: vit D
availability, VDREs accessibility, and VDR expression levels. All these actions are regulated
by environmental, genetic, and epigenetic factors. From the environmental factors, sun
exposure, pollution, diet, and infection are able to regulate the VDR mainly by altering the
levels of vit D [84,85].
VDR expression is differently correlated with inflammatory cytokines expression
and miRNAs regulation, mainly miRNA-21, -214, and -125. A single nucleotide poly-
morphism of the VDR gene constitutes a risk factor for coronary artery disease [
86
]. In

Nutrients 2023,15, 767 8 of 13
macrophages, which are essential immune cells during the vascular inflammatory re-
sponse, upregulation of miRNA-155 is associated with LPS induced hyper-inflammatory
process by the inhibition of suppressor of cytokine signaling 1 (SOCS1). On the contrary,
1,25-dihydroxycholecalciferol-VDR signaling has been demonstrated to downregulate BIC
gene transcription by blocking the activation of NF-
κ
B, leading to decreased miRNA155 lev-
els and increased SOCS1 translation [
87
]. In addition, upregulation of epithelial VCAM-1,
ICAM-1, and IL-6 is related to inflammation and atherogenesis in an
in vivo
mouse model
of VDR deletion [
88
]. VDR is directly involved in the suppression of NF-
κ
B activation,
which may explain, at least in part, the VDR-mediated anti-inflammatory effects of vit D in
cardiovascular pathologies [
88
,
89
]. Most of the studies on vit D and vascular inflammatory
process focus on immune cells such as monocytes/macrophages or T cells activated by LPS.
In this context, Gynther and coworkers demonstrated that LPS-treated human monocytes
exposed to vit D (10 nM, cholecalciferol) downregulated the pro-inflammatory IL-12B gene
by VDR-RXR binding. By the recruitment of co-repressor NCOR2/SMRT and HDAC3,
a significant reduction in histone 4 acetylation and an increase in histone 3 trimethyla-
tion were observed at the IL-12B promoter [
90
]. Additionally, VDR-RXR binding to the
nuclear factor needed for the activation of T cell (NFAT) sites caused the dissociation
of acetylated histone H4 from IL17A promoter and recruitment of HDAC2 to the NFAT
sites, thus supporting the role of 1,25(OH)2D in attenuating the pathogenesis of vascular
inflammation [
91
]. By binding to the TLR4, LPS triggers mitogen-activated protein kinases
(MAPK) and NF-
κ
B signaling activation, causing the expression of TNF, IL1B, IL6, and
IL8 genes [
21
]. Curiously, when monocytes obtained from patients with type 1 diabetes
mellitus with microvascular complications were pre-incubated with vit D (0.1
µ
mol/L), a
reduction in their LPS-activated TLR4 expression and cytokine levels was observed [
92
].
Moreover, Zhang et al. [
93
] found that vit D dose dependently (15–70 ng/mL) inhibits
LPS-induced cytokine synthesis by the upregulation of MAPK phosphatase 1 (MKP-1) in
human monocytes and murine bone marrow-derived macrophages. Notably, increased
VDR binding to a putative VDRE in the MKP-1 promoter and histone H4 acetylation
close the VDRE site led to MAPK inactivation, thereby reducing p38 activation and cy-
tokine production. Another study demonstrated that 1,25(OH)2D has no distinguishable
effect on p38 phosphorylation in macrophages, suggesting that the downregulation of
the pro-inflammatory COX-2 happens in a MAPK-independent manner. In this study,
vit D blocked Akt/NF-
κ
B/COX-2 axis-mediated proinflammatory cytokines by binding
VDR to a functional VDRE in the thioesterase superfamily member 4 (THEM4) promoters,
thereby helping to the cardiovascular protective effects of vit D [
94
]. Epidemiological
studies informed that vit D deficiency (25(OH)D < 15 ng/ mL) could be considered a sign of
cardiovascular risk, mostly in people with hypertension [
95
]. In fact, there is an association
between vit D deficiency and inflammatory disorders in humans; this is so usual it is
considered a global issue [
96
]. Recently, Wimalawansa [
97
] recapitulated the role of vit
D on oxidative stress, epigenetics, gene expression, inflammation, and the aging process.
These aging-related processes seem to happen at lower rates in individuals with normal
vit D status. Severe vit D deficiency (25(OH)D
≤
10 ng/mL) seems to be associated with
methylation in leukocyte DNA, mainly in MAPRE2 and DIO3 genes, both correlated with
tumor development [
98
]. All these studies support the genetic and epigenetic modulation
of vit D and its relevance in inflammation.
4. Conclusions
It is common to associate vit D with skeletal homeostasis. However, new roles are
constantly emerging for vit D with closer investigations. VDR is linking at hundreds of
sites in the genome and is associated with the regulation of more than 60 genes. Moreover,
vit D (and its active derivatives) not only play a role in the genetic regulation of many
genes, but also in the epigenetic regulation. In fact, the epigenetic machinery can be altered
by vit D, acting through multiple genetic mechanisms. Gene expression can be modified by

Nutrients 2023,15, 767 9 of 13
numerous miRNAs working as epigenetic modulators of VDR, also by methylation and
histone acetylation/deacetylation [2].
Vit D is involved in processes related to the development and progression of some
inflammatory diseases, and has the ability to alter serum levels of both proinflammatory
and anti-inflammatory mediators.
Beyond the known intimate relationship between vit D and the gastrointestinal tract,
we can highlight a bidirectional communication between the VDR and the intestinal micro-
biota. Both participate in an autoregulation in which different types of post-transcriptional
mechanisms and their relationship with intestinal permeability are also involved.
Moreover, vit D has protective effects in CKD and hypertension, and one of the mechanisms
by which it carries out this function is through the alteration of the RAAS system.
On the other hand, with new research findings, more insight is being obtained about
the relationship between vit D and different pathologies of the nervous system. Most
of these are focused on vit D and its relationship with oxidative stress. We know that
oxidative stress is one of the best-known starting points of different neuroinflammatory,
neurodegenerative, and neuropsychiatric processes. It is clear that vit D has implications
in general health and this fact invites researchers to continue looking for functions and
delving into the study of other physiological actions and how its deficiency is associated
with numerous pathologies beyond those explained here, such as diabetes, obesity, and
cancer. Thus, we speculate that vit D, now considered as calciotropic hormone, may later
be considered a hormone with multisystemic action.
Author Contributions:
Conceptualization, L.M. and W.M.; writing—original draft preparation, L.M.,
M.F.H., F.A.A. and W.M.; writing—review and editing, V.M.M.G. and S.G.M. All authors have read
and agreed to the published version of the manuscript.
Funding:
This research was funded by grants from Secretaría de Investigación, Internacionales y
Postgrado, Universidad Nacional de Cuyo (grant number 06/J044-T1), and from ANPCyT (Agencia
Nacional de Promoción de la Ciencia y la Tecnología, grant number PICT 2020 Serie A 4000), both
awarded to W. Manucha.
Institutional Review Board Statement: No application.
Informed Consent Statement: No application.
Data Availability Statement: No application.
Conflicts of Interest: The authors declare no conflict of interest.
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