Multiple sclerosis (MS) is one of the complex diseases.
Genetics, environmental and emotional factors have shown to play
essential roles in evoking the disease pathology. More interestingly,
epigenetic factors were established as major influencers of the
disease severity [1] Of those epigenetic factors; the microRNA
(miRNA) plays a fundamental function in MS pathogenicity. MiRNA
are small noncoding RNA molecules with a size of approximately
22 nucleotides involved in post-transcriptional regulations of the
genes [2-5]. In one of the first published papers on the relation
between MS and miRNA, Otaegui and his group found differential
miRNA profile between MS patient and healthy volunteers when
analyzing 364 peripheral blood mononuclear cells (PBMC) samples.
More so, they found that even between MS patients, miRNA profile
can differentiate between remissions and relapses stages [6]. One
of the most attractive miRNA associated with MS was the miR-155.
In 2009, Junker et al have for the first time identified miR-155
upregulation in active MS lesions [7]. Subsequently, many have
established the role of this miRNA in relapsing stages of MS and
experimental autoimmune encephalomyelitis (EAE) [4,8-15].
MiR-155 was of interest due to its important roles in immune
system regulation. This miRNA has been proven to target the
suppressor of cytokine signaling -1 (SOSC1); a negative regulator of
cytokines signaling. It was also proven to induce T- cell differentiation
along the T-helper 17 (Th17) and T-helper 1 (Th1) cells lines [16-
19]. MiR-155 was, moreover, documented to target transcription
factor Ets1; a negative modulator of Th17 differentiation [20].
Additionally, it targets CD47; a molecule involved in self-recognition
and protect cells from phagocytosis [21]. It, more so, suppresses src
homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1);
a known negative inhibitor of pro-inflammatory pathways to
macrophages (MØ) and dendritic cells (DCs) [20]. Besides all that,
miR-155 can suppress essential neuro-steroids in the white matter
of MS cases [21,22]. And was noted to increase the tumor necrosis
factor - α (TNFα) and monocyte chemoattractant protein-1 (MCP1)
expression in a toll-like receptor -4 (TLR4)-dependent manner,
resulting in neuro-inflammation in the cerebellum [23].
Captivatingly, several environmental factors associated with
MS pathogenicity were proven to regulate this miRNA expression.
Vitamin D deficiency, Epstein-Barr virus (EBV), obesity, alcohol
consumption and cigarette smoking were all associated with MS
pathogenicity previously and have been associated with miR-155
[19]. Vitamin D, one of the major environmental protective agents
against MS, was found to attune MØ induced inflammation via
targeting miR-155 [24]. While EBV, one of the major risk factors
for MS, can upregulate this miRNA [25-33]. Obesity, another MS
risk factor, is characterized by the over-accumulation of proinflammatory
MØ (M1) [34-35]. M1 cells are marked by the
increased miR-155-5p and it is thought that this miRNA control
M1 polarization [36-37]. In an interesting article, miR-155 were
found to be upregulated in the brain by alcohol diet, another MS
stimulator [23,38]. Alcohol consumption was recorded to provoke
neuro-inflammation in mice through miR-155 induction [23].
More so, cigarette smoke-induced inflammation could result from
the upregulation of miR-155 [39]. Those points may indicate the
importance of this miRNA and the need to be further analyzed
regarding environment-induced MS.
This miRNA has been documented to manipulate MS patients’
body by several means. When investigating MS, Moore et al
have found significant increase of miR-155 in circulating CD14+
monocytes and active lesion (CD68+ cells) comparing to healthy
controls cells. They have proven the role of miR-155 as a proinflammatory
regulator of macrophages and microglia polarization.
Also, in their report, they found that miR-155 transfected in myeloid
cells can increase TNFα, M1-associated surface markers (CD80,
CD86, and CCR7) and enhance the allogeneic T-cell responses [40].
Jevtić and his group, subsequently, have indicated the role of miR155
in re-activation of encephalitogenic CD4+ T cells in EAE rats
[41]. Interestingly, Lopez-Ramirez and his colleagues claimed miR155
as a negative regulator of BBB function that targets cell-cell
complex molecules (annexin-2 and claudin-1) and focal adhesion
components (DOCK-1 and syntenin-1). In their report, miR-155
increased expression could mimic cytokine-induced alterations in
junctional organization and increase the permeability, while
inhibition of miR-155 could prevent cytokine-induced increase in
the permeability [42]. While, Cerutti et al indicated the role of brain
endothelium miR-155 up-regulation in extravagating the adhesion
to award monocyte and T cells. This was partially caused by the
miR-155 modulation of leukocyte migration include intercellular
adhesion molecule-1 (ICAM-1) and vascular cell adhesion
molecule-1 (VCAM-1) [42].
In Noorbakhsh et al paper, miR-155 was associated with the
suppression of allopregnanolone, an important neurosteroid,
in both MS patient and EAE models. Supplementation of this
neurosteroid in EAE models was accompanied by decreased
neuropathology, including neuroinflammation, myelin and axonal
injury and reduced neurobehavioral deficits [43]. Notably, Singh
et al identified miR-155 as a biomarker for MS that can increase
in expression 6 days before the onset of the EAE disease in urine
exosomes, plasma, and spinal cord; emphasizing it is role in early
pathogenicity of EAE [44]. In 2011, Paraboschi and his group have
identified the genetics factors that associate miR-155 with MS; a
haplotype of 3 SNPs mapped in the mir-155 gene (P = 0.035; OR
= 1.36, 95% CI = 1.05-1.77) [9]. Although, Quinn et al signify the
role of the transcription factor Ets2 as a key regulator in miR-155
inflammatory response and that Ets2 deficient mice displayed
defective immunological responses [45]. Ets2 was unfortunately
not analyzed previously for its’ relation to MS.
It is worth noting that while Waschbisch et al noted that
glatiramer acetate (GA) treatment, the first approved treatment
for MS, has no effect on this miRNA, Singh et al noted that miR-155
is one of the GA-responsive biomarkers [8,46-47]. Fortunately,
natalizuma, fingolimod and Dimethyl fumarate (DMF) could regulate
the miR-155 expression in MS patients [48,10]. Interestingly,
high-dose ascorbic acid (AA) monotherapy can also modulate
miR-155 [49]. One captivating article had discussed the effect of
Autologous hematopoietic stem cell transplantation (AHSCT) on
regulating miRNA profile; of which miR-155 [50]. In conclusion,
miR-155 is one of MS biomarkers that can be detected in patient
body fluids before the onset of the disease, contribute to disease
pathogenicity and have been documented to increase in expression
during relapses stages. This miRNA contributes to inflammation,
BBB infiltration, and neuropathology processes. It is thought that
MS patient genetics factors can affect the expression of this miRNA.
Fortunately, current MS treatments have been documented to
modulate the expression of miR-155. MS pathology and the true
modulation effect of MS modulators are still questionable, here we
explore one side of the story in aim to fully understand the whole
picture.
Author Contribution: Eiman M. A. Mohammed alone is
responsible for the content and writing of this paper. The author
has read and approved the final manuscript