REVIEW doi: 10.1111/sji.

12261
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The Role of MicroRNAs in Autoimmune Diseases with

Skin Involvement
X. Deng*a, Y. Su*a, H. Wu*, R. Wu*, P. Zhang*, Y. Dai†, T.-M. Chan‡, M. Zhao* & Q. Lu*

*Hunan Key Laboratory of Medical Epigenetics,
Department of Dermatology, Second Xiangya
Hospital, Central South University, Changsha,
Hunan, China; †Clinical Medical Research
Center, The Second Clinical Medical College of
Jinan University (Shenzhen People’s Hospital),
Shenzhen, Guangdong, China; and ‡Division of
Nephrology, Department of Medicine, Queen
Mary Hospital, University of Hong Kong, Hong
Kong, China
Received 24 August 2014; Accepted in revised
form 10 November 2014
Correspondence to: M. Zhao and Q. Lu, Second
Xiangya Hospital, Central South University,
#139 Renmin Middle Road, Changsha, Hunan
410011, China. E-mails: zhaoming6260@gmail.
com; qianlu5860@gmail.com
a munity are elucidated to provide information for clinical implications.
These authors contributed equally to this work.
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively
modulate gene expression by binding to the 30 untranslated region (UTR) of
target messenger RNAs (mRNAs), which leads to the degradation or translational
repression of their target mRNAs. Previous research on miRNAs has revealed a
new paradigm of gene regulations and pathways involved in the pathogenesis of
autoimmune disorders and malignant diseases. The roles of miRNAs in cellular
processes, including cell differentiation, proliferation, apoptosis and immune
functions, are not clearly understood. MiRNAs are easily detected in a variety of
sources, including tissues, serum and other body fluids, and this make them a
good biological sample for pathogenic studies and disease biomarker develop-
ment. This review encompasses the current understanding of the roles of miRNAs
in autoimmunity and the cellular and molecular mechanisms of miRNAs in
various autoimmune diseases (AIMDs). Specifically, we focus on the target genes
of miRNAs and the biological processes associated with autoimmune diseases
with skin involvement, including systemic lupus erythematosus, psoriasis,
systemic sclerosis, Behcet’s disease and dermatomyositis. In addition, the
diagnostic and therapeutic relevance of miRNAs that are involved in autoim-

specific miRNAs have been identified to be important

Introduction
Generally, autoimmune diseases (AIMDs) are believed to be
caused by a combination of genetic predisposition and
environmental exposure [1]. However, concordance rates for
AIMDs in monozygotic twins are <50%, and significant
genetic associations are found only in a minority of
patients, which strongly suggests that apart from genetic
factors, other mechanisms are involved in the pathogenesis
of autoimmunity [1, 2]. It is generally accepted that
environmental factors, including dietary habits, chemicals
and hygienic conditions, partially modulate AIMDs sus-
ceptibility through epigenetic changes [2]. Epigenetic
modifications are non-genetic factors that are defined as
stable and heritable alterations in gene expression and
cellular function that do not involve changes to the original
DNA sequence [3]. MiRNAs together with DNA meth-
ylation and histone modifications are recognized as three
main epigenetic modifications [4]. To date, numerous
studies have provided evidence that miRNAs play a critical
role in the regulation of immune responses and immune
cell development. Currently, a relatively small number of
regulators of immune system [5].
MicroRNAs (MiRNAs) consist of a class of small,
approximately 22-nucleotide-long, endogenous RNAs that
negatively regulate coding gene expression and represent a
large family of endogenous non-coding RNAs that com-
prise a fundamental layer of post-transcriptional regulation
of gene expression in animals and plants [6]. The first
miRNA with homology to humans, let-7, was discovered
in 2000 in the nematode Caenorhabditis elegans [7].
Subsequently, over 1000 predicted miRNAs in the human
genome have been forecast to regulate the expression of
approximately 30% of all human genes. A single miRNA
can modulate hundreds of target genes by suppressing
translation, mediating mRNA segmentation or causing
RNA destabilization [8]. In contrast, multiple miRNAs
can cooperate to bind to and regulate a single target gene.
The biogenesis and maturation of miRNAs have been
intensely investigated in the past decade, but the under-
lying molecular mechanism is elusive. MiRNAs that
originate in the cell nucleus are transcribed as a huge
double-stranded primary transcript by RNA polymerase II.

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154 microRNAs in autoimmune skin diseases
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Primary miRNAs undergo maturation in two main steps.
First, Drosha (also known as ribonuclease III) and Pasha
convert this precursor into a double-stranded miRNA
precursor of ~70 nucleotides (pre-miR), which is next
transported to cytoplasm by Exportin 5 [6, 9]. Another
ribonuclease III in cytoplasm, called Dicer enzyme,
processes this precursor into mature miRNA duplexes,
which interact after strand separation by the Argonaut
protein at the core of the multiprotein RNA-induced
silencing complex (RISC) to generate miRNAs [10].
Mature miRNAs bind to the 30 UTR of target mRNAs,
which results in degradation or translational repression [9].
This regulation results in a significant reduction in target
gene protein levels and biological activities [6].
MicroRNAs impair protein expression levels through
two major mechanisms. One mechanism is direct inter-
ference of translation from mRNA to protein via attachment
of antisense sequences to specific complementary mRNA
targets. An inhibition of the initiation of ribosome drop-off,
stalled elongation and/or cotranslational protein degrada-
tion plays central roles in this mechanism. The second
mechanism involves the direct degradation of targeted
mRNAs by miRNAs. The net effect of both mechanisms on
miRNA activities is repression of targeted gene expression
[11, 12]. It has been reported that miRNAs are expressed in
immune cells and virtually impact all aspects of immune
responses. MiRNAs possess physiological functions and play
a critical role in human immune system. Abnormal miRNA
expression has been reported to lead to pathological
conditions that involve immune responses [6].
This review covers current knowledge on the crucial
roles of miRNAs in the pathogenesis of autoimmune
diseases with skin manifestations and highlights directions
for future research and potentials for translation of basic
research into clinical application.
Roles of miRNAs in autoimmunity
Autoimmunity refers to a pathogenic state in which the
immune system fails to recognize self-antigens and tissues,
which results in an immune response against a person’s own
cells and tissues through various immune constituents,
including autoreactive antibodies and immune-mediated T
cells [13]. This abnormal response to one’s own tissue
antigens has several presentations that are now categorized
as distinct types of disease phenotypes that vary depending
on the tissues and antigens being targeted [14]. Dysregu-
lated miRNA expression might cause serious complications
in the immune system [13], and increasing evidence has
revealed a critical role of miRNAs in the development of
autoimmunity.
Given that miRNAs play key roles in the regulation of
immune system, it is not surprising that recent studies
revealed links between miRNA dysfunction and autoim-
munity (Table 1). Aberrant miRNAs expression in
X. Deng et al.
pathological conditions influenced disease status through
the regulation of related molecular pathways [13]. For
example, one group of researchers discovered an advanced
role of miR-101 in a signalling pathway of autoimmunity in
T lymphocytes of the roguin mutant mice (sanroque mice).
Roquin normally regulates the expression of inducible T cell
costimulator (ICOS) by promoting the degradation of
ICOS mRNA [15]. However, lacking this regulation in
sanroque mice contributes to an accumulation of lympho-
cytes and autoreactivity that is associated with a lupus-like
disease. MiR-101 is required for the Roquin-mediated
depletion of ICOS mRNA, and the induction of mutations
into the miR-101 binding sites in the 30 UTR of ICOS
mRNA hindered the repressive [15]. This group discovered
an important miRNA-mediated regulatory pathway that
restrained lymphocyte accumulation and autoimmunity.
Furthermore, several studies have given compelling
evidence for a crucial role of miRNAs in regulatory T (Treg)
cell function and the prevention of autoimmunity [16–18].
Treg cells are critical for maintaining self-tolerance and
immune balance. The transcription factor forkhead boxP3
(Foxp3) is essential for maintaining the transcriptional
programme of Treg cells [19]. One study demonstrated that
Treg cell function was safeguarded by a Dicer-dependent
miRNA pathway [16]. Therefore, miRNAs preserve the
Treg cell functional programme. This result was confirmed
in one study that Dicer-deficient Treg cells lacked
suppression activity in vivo and that Dicer-deficient mice
rapidly developed a lethal systemic autoimmune disorder
[17]. The role of miRNAs in the development and death of
Treg cells is highlighted in this setting.
Another group further identified that the autoimmune
disorder that occurred in MRL/lpr mice was associated with
the simultaneous appearance of Dicer insufficiency and
miR-155 overexpression, which suggests a role of Dicer
and miR-155 in Treg defects in lupus [18]. These studies
indicate a pivotal role for miRNAs in maintaining the
stability of differentiated Treg cell function under inflam-
matory conditions in vivo and the prevention of autoim-
munity [16–18].
MiRNAs in autoimmune diseases with skin
involvement
MicroRNAs are differentially expressed in AIMDs, and
they can moderate autoimmune response and involve in
AIMDs development [20]. Since the discovery of miRNAs,
many studies have revealed that miRNAs play an impor-
tant role in AIMDs [5, 13, 20] (Table 1).
MiRNAs and systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a systemic autoim-
mune disorder with unknown aetiology that can affect
virtually multiple organs. SLE is characterized by
Scandinavian Journal of Immunology, 2015, 81, 153–165
X. Deng et al. microRNAs in autoimmune skin diseases 155
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Table 1 Aberrant miRNA expression in autoimmune skin disease..

Expression
Diseases MiRNAs Tissues/cells level Targets Effects Refs

SLE MiR-146a PBMC from patients with SLE ↓ IRF-5 Upregulation of type I IFN [22]
STAT-1 expression
MiR-125a T cells from patients with SLE ↓ KLF13 Upregulation of RANTES [37]
expression
MiR-148a CD4+ T cells from patients ↑ DNMT3B DNA hypomethylation [32, 39]
with SLE DNMT1 Upregulation of CD70 and
LFA-1 expression
MiR-155 Treg cells in MRL/lpr mice ↑ CD62L Regulation of Treg cell phenotype [18, 28, 30]
PBMCs from juvenile SLE Ets-1 Correlation with anti-dsDNA
antibody production
Correlation with SLEDAI score
and proteinuria
MiR-21 CD4+ T cells from MRL-lpr ↑ PDCD4 Correlation with SLEDAI score [24, 32]
mice and patients with SLE RASGRP1 DNA hypomethylation
MiR-126 CD4+ T cells from patients ↑ DNMT1 T cell and B cell hyperactivity [23]
with SLE DNA demethylation
MiR-29b CD4+ T cells from patients ↑ SP1 DNA hypomethylation [40]
with SLE Upregulation of CD11a and
CD70 expression
MiR-142-3p/5p CD4+ T cells from patients ↓ SAP, CD84, T cell [36]
with SLE and IL-10 overactivation
and B cell hyperstimulation
Histone modification and DNA
methylation
PS MiR-203 Keratinocytes from patients ↑ SOCS3, TNF-a Modulation of cytokine expression [45, 54, 56]
with PS and IL24 Enhancement of keratinocyte
differentiation
MiR-146a Skin lesion and PBMC of ↑ IRAK1, TRAF6 Correlation with IL-17 expression [57, 58]
patients with PS TNF-a and Involvement in innate immune
IL-1b response
MiR-369-3p Serum samples and skin tissues ↑ ND Positive linear relation with [51]
from patients with PS PASI scores
MiR-125b Keratinocyte from patients ↓ TNF-a and Modulation of keratinocyte [45, 52, 62]
with PS FGFR2 proliferation and its
differentiation
Involvement in innate immune
response
MiR-31 Keratinocyte from patients ↑ STK40 Contribution to skin inflammation [48]
with PS Regulation of cytokine expression
Promotion of inflammation
MiR-21 T cells from patients with PS ↑ ND Contribution to skin inflammation [49, 60, 61]
Epidermal lesions of patients ↑ Reduction epidermal TIMP-3
with PS expression
MiR-210 CD4+ T cells from patients ↑ FOXP3 Dysregulation of Immune [50]
with PS function
SSc MiR-21 Skin samples and FBs from ↑ SMAD7 Promotion of fibrosis [67]
patients with SSc
MiR-145 Skin samples and FBs from ↓ SMAD3 Upregulation of SAMD3 expression [67]
patients with SSc
MiR-29b Skin samples and FBs from ↓ COL1A1 Upregulation of COL1A1 expression [67]
patients with SSc Suppression of fibrosis
MiR-92a FBs or serum from patients ↑ MMP-1 Promotion of fibrosis [74]
with SSc
MiR-7 FBs from patients with SSc ↑ ND Suppression of [75]
collagens expression
MiR-29a FBs from patients with SSc ↓ ND Suppression of fibrosis [69]
MiR-196a FBs and serum from patients ↓ ND Promotion of fibrosis [66, 72]
with SSc

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156 microRNAs in autoimmune skin diseases X. Deng et al.
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Table 1 Continued.

Expression
Diseases MiRNAs Tissues/cells level Targets Effects Refs

MiR-129-5p FBs from patients with SSc ↓ ND Downregulation of type I [73]

collagen expression
MiR-150 FBs and serum from patients ↓ ND Suppression of fibrosis [66, 76]
with SSc
DM MiR-206 Serum and PBMCs of patients ↓ KLF Enhancement of TH17 [79]
with DM cells frequency
MiR-223 Skin lesion and serum of ↓ PKCvarepsilon Relation with clinical [80]
patients with DM manifestation of DM
MiR-126 Muscle and blood samples of ↓ ND Upregulation of VCAM-1 [82]
untreated Juvenile patients expression
with DM
MiR-7 Skin lesion and serum of ↓ ND ND [81]
patients with DM
BD MiR-146a PBMCs from patients with BD ↓ ND Association of rs2910164 [85]
of miR-146a
MiR-155 PBMCs and DCs from patients ↓ TAB 2 Modulation of cytokines [86]
with BD expression

SLE, Systemic lupus erythematosus; PS, psoriasis; SSc, systemic sclerosis; DM, dermatomyositis; BD, Behcet’s disease; ↑, increased; ↓, decreased; ND, not
determined; PBMCs, peripheral blood mononuclear cells; IFN, interferon; IRF-5, interferon regulatory factor 5; STAT-1, signal transducer and activator of
transcription 1; DNMT1, DNA methyltransferase 1; LFA-1, lymphocyte function-associated antigen 1; KLF13, Kruppel-like factor 13; RANTES, an
inflammatory chemokine; PDCD4, a selective protein translation inhibitor; SLEDAI, SLE Disease Activity Index; SAP, signalling lymphocytic activation
molecule associated protein; IL-10, interleukin-10; SOCS-3, suppressors of cytokine signalling 3; TNF-a, tumour necrosis factor; IRAK1, IL-1 receptor-
associated kinase 1; TRAF6, TNF receptor-associated factor 6; PASI scores, psoriasis activity severe index (PASI) scores; TIMP-3, tissue inhibitor of matrix
metalloproteinase 3; FGFR2, fibroblast growth factor receptor 2; FOXP3, forkhead boxP3; COL1A1, collagen type 1, alpha 1; PKCe, protein kinase C
varepsilon; VCAM-1, vascular cell adhesion molecule 1; DCs, dendritic cells; TAB 2, TGF-b-activated kinase 1 binding protein 2; Refs, References.

autoantibodies, immune complexes and self-reacting lym-
phocytes. Autoreactive autoantibodies (e.g. anti-dsDNA)
and the deposition of complement-fixing immune com-
plexes are prominent causes of the inflammation and
damage to multiple organs in patients with SLE [21].
Studies of miRNA expression profiles in patients with
SLE reveal the biological and clinical relevance of
miRNAs in SLE. An initial effort used TaqMan microR-
NA assays to identify the expression of 156 miRNAs and
found that there were 42 miRNAs differentially expressed
in peripheral blood mononuclear cells (PBMCs) in 52
Chinese patients with SLE compared to controls. Among
these miRNAs, 7 miRNAs (miR-31, miR-95, miR-99a,
miR-130b, miR-10a, miR-134 and miR-146a) were
significantly lower in patients with SLE [22]. In addition,
in our previous study, we found that six miRNAs,
including miR-1246, miR-574-5p, miR-1308, miR-638,
miR-7 and miR-126, were upregulated, and five miR-
NAs, including miR-142-5p, miR-142-3p, miR-31,
miR-186 and miR-197, were downregulated in CD4+ T
cells from 30 Chinese patients with lupus compared to 20
healthy subjects [23]. Another analysis of 365 miRNAs in
PBMCs from 34 Greece patients with lupus and 20
normal controls identified 14 downregulated miRNAs
and 13 upregulated miRNAs in patients compared to
controls [24]. Among these abnormally expressed miR-
NAs, many have been implicated to act as inhibitors of
numerous mRNAs involved in the process of SLE
development, suggesting that dysregulated expression of
miRNAs plays an important role in the pathogenesis of
SLE (Table 1).
MiR-146a in SLE
A recent study that identified miR-146 as a key player in
innate immunity was the first attempt to demonstrate the
importance of miRNA in immune regulation [25]. MiR-
146a negatively regulated the type I IFN pathway by
targeting interferon regulatory factor 5 (IRF-5), signal
transducer and activator of transcription 1 (STAT-1) [22].
Type I IFN displays a critical role in the pathogenesis of
SLE. Type I IFN, which is mainly produced by plasma-
cytoid dendritic cells (pDCs), promotes T cell prolifera-
tion and skews the differentiation of autoreactive T cells,
which results in an elevated production of autoantibodies
by B cells [26]. Decreased expression of miR-146a in
PBMCs was thought to contribute to the enhanced
production of type I IFN in human lupus, including
IFNa/b, in response to the activation of Toll-like receptor-
7 (TLR-7). Therefore, there is a negative correlation
between miR-146a expression and disease activity/IFN
scores. Moreover, the expression of miR-146a in lupus
patients with proteinuria is significantly lower than in
those without proteinuria, which suggests that a downre-
gulation of miR-146a is linked to the clinical manifesta-
tions of SLE [22].

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MiR-155 in SLE
Upon activation, miR-155 is expressed in several types of
immune cells, including B and T cells, macrophages and
dendritic cells, indicating that it might play a role in the
phenotype, activation or functions of these cells [27]. The
TLR2 (Toll-like receptor 2)/MyD88 (myeloid differentia-
tion factor 88)/miR-155 pathway has been found to be
pivotal for HMGB1 to confer anti-dsDNA antibody
induction, and Ets-1 was a functional target of miR-155
in the induction of anti-dsDNA antibody by circulating
DNA-containing immune complexes, suggesting that the
crucial role of HMGB1 in autoantibody production
mediated by the TLR2/MyD88/miR-155/Ets-1 pathway.
In addition, the expression of miR-155 and Ets-1 has been
found to correlate with anti-dsDNA antibody production
in patients with SLE [28]. In the death receptor deficient
(Faslpr) lupus-prone mouse model, another group showed
that ablation of miR-155 reduced autoantibody responses
with a reduction of kidney inflammation and a decrease in
serum IgG [29]. Recent finding showed that miR-155 was
significantly downregulated in PBMCs from juvenile SLE
than healthy controls. In SLE, miR-155 expression was
negatively correlated with SLE Disease Activity Index
(SLEDAI) score and proteinuria, and it was positively
correlated with white blood cell count. Forced expression of
miR-155 led to decreased expression of PP2Ac (the
catalytic subunit of PP2A) mRNA and increased IL-2
release in cultured-stimulated PBMCs, which suggests the
possible role of an miR-155-PP2Ac loop in regulating IL-2
release and miR-155 as a potential therapeutic target in
juvenile SLE disease through relieving IL-2 from the
inhibitory role of Protein phosphatase 2A (PP2A) [30].
MiR-21 in SLE
MiR-21 has been reported to be upregulated in CD4+ T cell
from patients with SLE compared with controls, positively
correlated with SLE disease activity. Silencing miR-21
expression reversed the activated phenotype of T cells from
patients with SLE. On the other hand, overexpression of
miR-21 in normal T cells led to acquisition of an activated
phenotype. Investigation of putative gene targets showed
that PDCD4 (a selective protein translation inhibitor) was
suppressed by miR-21 and PDCD4 expression was decreased
in active SLE [24]. Another group found that miR-21
expression in lupus B and T cells was upregulated and
silencing of miR-21 using a tiny seed-targeting LNA
derepressed PDCD4 expression in B6.SLE123 T cell. In
addition, treatment with anti-miR-21 altered CD4/CD8+ T
cell ratio and reduced Fas receptor-expressing lymphocyte
populations. The fold change of miR-21 expression in
B6.Sle123 B lymphocytes positively correlated with the age
of mice and thus with severity of their disease compared to
controls [31]. Another study confirmed that miR-21
Ó 2014 John Wiley & Sons Ltd
microRNAs in autoimmune skin diseases 157
promoted DNA hypomethylation in lupus CD4+ T cells
by repressing DNA methyltransferase 1 (DNMT1) expres-
sion. Further experiments revealed that miR-21 indirectly
downregulated DNMT1 expression by targeting an impor-
tant autoimmune gene, RASGRP1 [32]. Plasma miR-21
level in patients with SLE was higher than that of healthy
controls and significantly correlated with the level of plasma
complement C3, C4 and serum uric acid in patients with SLE
[33].
MiR-142-3p/5p in SLE
MiR-142, a T cell-specific miRNA [34], is known to play a
role in regulating T cell development. MiR-142 locus
produces 2 transcripts: miR-142-5p is expressed from the
50 arm of the locus, and miR-142-3p is expressed from the
30 arm [35]. Our group revealed that miR-142-3p and
miR-142-5p were significantly downregulated in SLE
CD4+ T cells compared with healthy controls. MiR-142-
3p targets members of the signalling lymphocytic activa-
tion molecule (SLAM) family, interleukin-10 (IL-10) and
CD84, and miR-142-5p targets SLAM-associated protein
(SAP) by interacting with their 30 -UTR. Downregulation
of miR-142-3p/5p increased the protein levels of CD84
and IL-10/SAP in healthy CD4+ T cells, leading to the
increased activation of T cell and IgG production from
cocultured B cells. In contrast, overexpression of miR-142-
3p/5p in SLE CD4+ T cells restored CD84 and IL-10/SAP
levels and reduced T cell activity and IgG production. In
addition, we demonstrated that the decreased miR-142-3p/
5p expression in patients with SLE may be due to the
upregulated H3K27 trimethylation and DNA methylation
within the regulatory region 500 bp upstream of the miR-
142 precursor sequence [36].
MiR-125a in SLE
MiR-125a is involved in one of the inflammatory chemo-
kine pathways in autoimmune disease that has been
proposed in the pathogenesis of lupus. MiR-125a nega-
tively regulates RANTES (an inflammatory chemokine)
expression by targeting Kruppel-like factor 13 (KLF13) in
activated T cells [37]. Previous studies have shown that
RANTES, which recruits CD4+ and CD8+ T cells, and
macrophages to inflammatory tissues, is detectable in
kidney tissues and initiates renal damage in MRL-Faslpr
mice [38]. Low expression of miR-125a in lupus T cells
contributes to the elevated expression of RANTES in SLE
[37], and it may be associated with renal inflammation in
lupus.
Other miRNAs in SLE
MicroRNAs, as one of the major epigenetic features,
interlink DNA methylation and histone modifications
158 microRNAs in autoimmune skin diseases
..................................................................................................................................................................
[36], target certain genes and regulate related pathways.
Currently,many studies have showed that miRNAs regu-
lates DNA methylation by targeting the DNA methyl-
transferase (DNMT) in SLE. For example, our study and
others’ previous studies confirmed that the dysregulation of
miR-126, miR-148a and miR-29b in CD4+ T cells from
lupus patients lead to DNA hypomethylation via targeting
DNMT [23, 32, 39, 40]. Initially, two studies identified
that miR-148a was upregulated in CD4+ T cells from
lupus individuals [32, 39]. Overexpression of miR-148a in
CD4+ T cells leads to DNA hypomethylation and increases
the expression of autoimmune-associated methylation-
sensitive genes, CD70 and lymphocyte function-associated
antigen 1 (LFA-1) via promoter demethylation [32]. MiR-
126 regulates DNA methylation in CD4+ T cells and
contributes to T cell autoreactivity in SLE by directly
targeting DNMT1, and miR-29b negatively regulates
DNMT1 expression by targeting sp1 in SLE T cells.
Similar to miR-148, miR-126 and miR-29b in T cells
downregulate DNMT1. Overexpressed miR-126 and miR-
29b caused DNA hypomethylation and an upregulation of
genes encoding CD11a (ITGAL) and CD70 (TNFSF7),
which contributed to T cell and B cell hyperactivity [23,
40].
MiRNAs and psoriasis
Psoriasis is an autoimmune skin disease characterized by
excessive proliferation and abnormal differentiation of
keratinocytes. Diagnosis is based on typical skin lesions
of erythematous scaling plaques, which are the results of
inflammatory infiltrates [41], and other manifestations in
nails and joints [42]. Aberrant immune responses mediated
by T cells, dendritic cells (DCs) and various immune-
related inflammatory cytokines and chemokines are
involved in psoriasis pathogenesis [43].
Differentially expressed miRNAs likely influence many
processes that are involved in psoriasis pathogenesis, such
as epidermal differentiation (miR-125b, miR-21, miR-
203), angiogenesis (miR-21, miR-31, miR-378) and
haematopoiesis (miR-142-3p) [44, 45]. The abnormally
upregulated or downregulated miRNAs levels play an
important role in the mechanisms underlying psoriasis.
Among these miRNAs, miR-203, miR-146a, miR-31,
miR-21, miR-210 and miR-369-3p are increased, and
miR-125b is decreased in psoriasis compared to controls.
These miRNAs regulate inflammatory autoimmune pro-
cess via distinct pathways or/and targets [45–53] (Table 1).
MiR-203 in psoriasis
MiR-203 is the first reported miRNA in psoriasis.
MiR-203 targets gene suppressors of cytokine signalling
3 (SOCS-3), which is involved in inflammatory responses
and keratinocyte functions [45]. As one of the most
X. Deng et al.
upregulated miRNAs in primary keratinocytes from
patients with psoriasis, miR-203 targets genes, including
tumour necrosis factor (TNF-a) and IL-24, which are two
pro-inflammatory cytokines that are upregulated in psori-
atic skin. Overexpression of miR-203 represses the expres-
sion of its target genes [54]. These findings suggest that
miR-203 fine-tunes cytokine signalling and may dampen
skin immune responses by repressing the expression of key
pro-inflammatory cytokines [54]. MiR-203 also reduces
the post-transcriptional level of IL-8 in primary human
keratinocytes under both resting conditions and after TNF-
a treatments [55]. The expression of miR-203 is under the
regulation of the protein kinase C (PKC)/activator protein-
1 (AP-1) pathway in human keratinocytes, and it is
necessary and sufficient for the initiation of the early steps
in human keratinocyte differentiation. Overexpression of
miR-203 in keratinocytes enhances keratinocyte differen-
tiation [56].
MiR-146a in psoriasis
MiR-146a is involved in innate immunity by regulating
the acute inflammatory response after pathogen recognition
by Toll-like receptors (TLRs) on monocytes or macrophag-
es [25]. MiR-146a was highly expressed in skin lesions and
PBMCs of patients with psoriasis but at low levels in
healthy skin, which suggests that miR-146a in the skin
was expressed by infiltrating cells. MiR-146a is also
positively correlated with IL-17 expression in skin lesions
and PBMCs from patients with psoriasis [57]. Moreover,
miR-146a regulates the pro-inflammatory TLR/MyD88
pathway by targeting IRAK1 (IL-1 receptor-associated
kinase 1) and TRAF6 (TNF receptor-associated factor 6),
and it is negatively related to activation of the type I IFN
or IL-1 regulatory signal network [25]. Pro-inflammatory
cytokines, such as TNF-a and IL-1b, also target miR-146a
expression [58]. TNF-a is an important mediator in
leucocyte–keratinocyte interactions in psoriasis and
enhances keratinocytes differentiation [59]. These data
indicate that inhibition of miR-146a may be a potential
therapeutic option in psoriasis.
MiR-21 in psoriasis
Besides SLE, miR-21 is also involved in the pathogenesis of
psoriasis. MiR-21 has been found to be upregulated in
dermal T cells and epidermal cells of patients with
psoriasis, which suppresses T cell apoptosis and contributes
to skin inflammation [49]. The degradation ratio of miR-
21 was significantly reduced in psoriasis samples compared
with unaffected skin. Tumour suppressor PAPD5 mediate
degradation of oncogenic miRNA miR-21 through a
tailing and trimming process and that this pathway is
disrupted in psoriasis and cancer. Hence, these findings
indicate that dysregulation of the miR-21 degradation
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pathway is a general feature in tumours as well as in
psoriasis [60]. Recent study has confirmed that miR-21
expression is increased in epidermal lesions of patients with
psoriasis and this leads to reduced epidermal TIMP-3
(tissue inhibitor of matrix metalloproteinase 3) expression
and activation of TACE (tumour necrosis factor-a-con-
verting enzyme)/ADAM17 (a disintegrin and metallopro-
teinase 17). The impaired transcriptional activity of Jun/
activating protein 1 (AP-1) causes the increased miR-21
expression in patient-derived skin samples and mouse
models of psoriasis, leading to activation of the interleukin-
6 (IL-6)/signal transducer and activator of transcription 3
(Stat3) pathway. The above suggests that targeting miR-21
may represent a potential therapeutic option for the
treatment of psoriasis [61].
MiR-125b in psoriasis
Another research group identified that miR-125b in skin
lesions of patients with psoriasis played an important role
in the regulation of keratinocyte proliferation and differ-
entiation, partially through the regulation of fibroblast
growth factor receptor 2 (FGFR2). The knock-down of
FGFR2 expression by siRNA suppressed keratinocyte
proliferation, but no effect on differentiation was observed
[52]. Loss of miR-125b in psoriasis skin may contribute to
hyperproliferation and aberrant differentiation of keratino-
cytes [52]. Furthermore, miR-125b also targets TNF-a,
which suggests that its downregulation in response to LPS
may be required for proper TNF-a production and for
miR-125b to play a role in innate immune response [45,
62].
Other miRNA in psoriasis
Recently, other miRNAs also have been found to be
involved in the pathogenic process of psoriasis. For
example, our research confirmed that miR-210 expression
was significantly increased in CD4+ T cells from patients
with psoriasis vulgaris, and FOXP3 is one of the target
genes [50]. Overexpression of miR-210 decreases FOXP3
expression and impairs the immunosuppressive functions
of regulatory CD4+ T cells from healthy controls. In
contrast, inhibition of miR-210 displays the opposite
effect. Upregulated miR-210 expression induces immune
dysfunction via FOXP3 in CD4+ T cells from patients with
psoriasis vulgaris [50].
MiR-31 has been found to be markedly overexpressed
in keratinocytes from patients with psoriasis. Further-
more, interference with endogenous miR-31 decreased the
ability of keratinocytes to activate endothelial cells and
attract leucocytes. Serine/threonine kinase 40 (STK40),
which is a negative regulator of NF-jB signalling, is a
direct target of miR-31. MiR-31 regulates cytokine/
chemokine expression via the targeting of STK40 in
Ó 2014 John Wiley & Sons Ltd
microRNAs in autoimmune skin diseases 159
keratinocytes. Moreover, overexpression of miR-31 con-
tributes to skin inflammation in psoriasis lesions by
regulating the production of mediators of inflammation
and/or fibrosis such as TGF-b, and leucocyte chemotaxis
to the skin [48].
One recent study showed that the expression of miR-
369-3p was increased in serum samples and skin tissues
from patients with psoriasis compared to healthy subjects.
MiR-369-3p levels in skin had a positive linear relation-
ship with psoriasis activity severe index (PASI) scores [51].
MiRNAs and systemic sclerosis
Systemic sclerosis (SSc) is a highly heterogeneous autoim-
mune disease that is characterized by microvascular
dysfunction, progressive fibrosis of the skin and/or internal
organs, and immune abnormalities [63]. As reviewed by
Gabrielli et al. [64], fibrosis is a prominent hallmark of
systemic sclerosis, and it results from the excessive
accumulation of extracellular matrix (ECM), ultimately
leading to the failure of affected organs, such as the kidney,
heart and lung [64].
The pathogenesis of SSc is still unknown, but it
involves complex interactions between genetic predispo-
sition and epigenetic modifications caused by environ-
mental factors [65]. MiRNAs, as one of the epigenetic
features, has been identified in skin fibroblasts and sera of
patients with SSc (Table 1). The aberrant expression of
miRNAs is likely to be the critical factor for pro- or
antifibrosis, and it is related to the initiation and
progression of pathophysiological processes of SSc [66].
For example, miR-21 promotes fibrosis, and miR-29,
150, 92a and 196a suppress fibrosis [66]. Studies of
miRNA expression are expected to support a similar
conclusion by identifying unique miRNA profiles in
patients with SSc, which reveals a biological and clinical
relevance between miRNA expression and SSc disease
severity. One study group identified that 42 miRNAs
were differentially expressed in diffuse cutaneous sclero-
derma (dSSc) and 60 miRNAs were altered in limited
cutaneous scleroderma (lSSc). A total of 21 miRNAs were
altered similarly in dSSc and lSSc [67]. Another study
group identified 24 differentially expressed miRNAs in
skin tissue from Chinese patients with SSc, including
nine upregulated miRNAs and 15 downregulated miR-
NAs, using miRNA microarray chip analysis [68]. Many
of these altered miRNAs were related to pathophysio-
logical processes of SSc and involved in autoimmune,
vascular and fibrotic processes (Table 1).
MiR-29 in SSc
MiR-29a and miR-29b, as a main part of miR-29 family,
were highlighted in recent. MiR-29a exerts antifibrotic
effects in several major fibrotic disorders, such as SSc [69].
160 microRNAs in autoimmune skin diseases
..................................................................................................................................................................
MiR-29a is significantly reduced in fibroblasts and skin
lesions from patients with SSc compared to healthy
controls. MiR-29a overexpression significantly reduces
the expression of collagen types I and III, which suggests
a unique negative role for miR-29a in SSc-related fibro-
genesis and its potential application as a putative thera-
peutic target [70]. TGF-b, IL-4 or platelet-derived growth
factor B (PDGF-B) reduced the levels of miR-29a in
fibroblasts, which further upregulated PDGF-B and TGF-b
[69, 70]. This positive feedback loop can lead to an
uncontrolled accumulation of ECM proteins. However,
inhibition of PDGF-B and TGF-b pathways restored the
levels of miR-29a in vitro and in a bleomycin model of SSc
in vivo [70]. In addition, miR-29b levels were decreased in
skin tissues and fibroblasts. The downregulation of miR-
29b was correlated with the upregulation of COL1A1
(collagen type 1, alpha 1) [67]. These studies suggest that
decreased miR-29 expression is involved in SSc tissue
fibrosis and that miR-29 suppresses fibrosis.
MiR-21 and MiR-145 in SSc
Several studies have demonstrated that aberrant expression
of miR-21 and miR-145 is involved in pathogenesis of SSc.
MiR-21 expression was upregulated and miR-145 was
downregulated in SSc skin samples and fibroblasts. Both
miRNAs regulate genes such as SAMD3, SMAD7 and
COL1A1 that are involved in fibrosis in SSc [67]. Up- or
downregulated protein levels of the SMAD family and their
cofactors could result in heightened fibrogenesis. TGF-b,
secreted by fibroblasts or myofibroblasts, plays a pivotal role
in fibrosis by directly mediating fibrosis and inducing the
transdifferentiation of mesenchymal cells to myofibroblasts
[71]. After stimulation with TGF-b, the level of miR-
21 expression was increased and the expression level of
SMAD7 was decreased. TGF-b also raises miR-145 expres-
sion and reduces mRNA level of SMAD3. Both miR-21 and
miR-145 may exert pro- or antifibrosis effects in SSc [67].
MiR-196a in SSc
It has been reported that MiR-196a expression is decreased
in SSc as measured using real-time PCR. Overexpression of
miR-196a reduces the expression of type I collagen in SSc
fibroblasts, and the inhibition of miR-196a results in the
overexpression of type I collagen in normal FBs. MiR-196a
expression in SSc fibroblasts was normalized by TGF-b
siRNA. Investigation of the regulatory mechanisms of type
I collagen expression by miR-196a may lead to novel
treatments using miRNAs [72].
Other miRNAs in SSc
Other miRNAs, such as miR-129-5p, miR-150, miR-92a
and miR-7, also play significant roles in the pathogenesis of
X. Deng et al.
SSc. One recent study validated that miR-129-5p was
down-expressed in SSc fibroblasts, and it can also be
upregulated by IL-17A expression, which reduces the
expression of type I collagen and connective tissue growth
factor [73]. However, miR-92a is upregulated in sera and
fibroblasts of SSc, and it downregulates the expression of
MMP-1, which is one target gene of miR-92a. The
stimulation of intrinsic TGF-b can also decrease miR-92a
expression. Moreover, miR-92a is also involved in the
pathogenesis of fibrosis in SSc [74]. Another research group
identified that the expression level of miR-7, which is
upregulated in SSc dermal fibroblasts in vivo and in vitro,
had an inhibitory effect on collagen expression [75]. One
new study demonstrated that miR-150 expression is also
decreased in fibroblasts and sera of patients with SSc.
Reduced expression of miR-150 increased type I collagen
expression via the induction of integrin b3. Treatment of
SSc fibroblasts with 5-AdC revealed that the miR-150
downregulation in these cells was caused by DNA
methylation [76].
The miRNAs identified above have been confirmed to
have pro- or antifibrotic effects in SSc via different
signalling pathways. Inhibiting the function of these pro-
fibrotic miRNAs through the use of specific miRNA
inhibitors and promoting antifibrotic miRNAs through
gene therapy or the use of specific miRNA mimics will
provide novel therapeutic options in the future.
MiRNAs and dermatomyositis
Dermatomyositis (DM), a subtype of rare inflammatory
myopathies, is characterized by symmetric proximal
muscle, truncal weakness and extra-muscular involvement,
such as cutaneous impairment [77]. As reviewed by
Nagaraju et al. [78], autoantibodies (especially anti-Jo-1,
anti-Mi-2), and pro- or anti-inflammatory cytokines, have
been detected in the serum of patients with DM.
The aetiology of DM is still obscure and many
hypotheses have been proposed, the most compelling of
which involves a combination of environmental and
genetic factors. MiRNAs, as one of the environmentally
induced epigenetic factors, have been reported to play an
important role in the pathogenesis of DM. This part of the
review summarized several miRNAs that are up- or
downregulated in DM skin (Table 1).
MiR-206 in DM
Recent report showed the association between frequency of
Th17 cells and the expression of miR-206 in the peripheral
blood of patients with DM [79]. They identified
CD3+CD8IL-17+ cells to distinguish Th17 cells from
PBMCs and found increased Th17 cells proportion and
enhanced secretion of IL-17 in DM PBMCs. At the same
time, the levels of KLF4, one positive regulators of Th17
Scandinavian Journal of Immunology, 2015, 81, 153–165
X. Deng et al.
..................................................................................................................................................................
differentiation, were also increased obviously in the PBMCs
from patients with DM. As expected, the augmented
expression of KLF4 was accompanied by the attenuated
expression of miR-206, a miRNA picking KLF4 as one of
its multiple targets. Furthermore, this study showed a
negative correlation between the percentages of Th17 cells
and the expression of miR-206 in patients with DM. These
findings collectively suggest that the augmented expression
of KLF4 mRNA may be caused by the attenuated
expression of miR-206, and the high level of KLF4
mRNA evokes the proportion of Th17 cells in patients
with DM.
MiR-223 in DM
Another group explored the expression pattern of miRNAs
in Gottron’s papules of patients with DM by miRNA PCR
array analysis and then evaluated the role of miRNAs in
the pathogenesis of Gottron’s papules. Among the several
miRNAs with changed expression, they identified miR-
223, which was significantly decreased in DM than that in
normal skin. Further research found an increased expression
of PKCe (protein kinase C varepsilon), one of the putative
target genes of miR-223, in the hyperproliferated epider-
mis of Gottron’s papules in patients with DM. A specific
inhibitor of miR-223 can induce cell proliferation, while
knockdown of PKCe by a specific siRNA can decrease cell
number, demonstrating that miR-223 is involved in the
keratinocyte proliferation via targeting PKCe. In this
study, they also detected the serum level of miR-223 in
patients with DM and found a significantly decreased level
of serum miR-223 was observed in patients with clinically
amyopathic DM, which was characterized by skin lesions
without muscle weakness, indicating that the decreased
serum miR-223 level may be associated with cutaneous
involvement of the disease. In addition, decreased serum
miR-223 levels tend to have more severe symptoms. Thus,
the serum miR-223 level might serve as new biomarker for
amyopathic DM, whose diagnosis is sometimes difficult,
especially in the absence of myositis or lung involvement
[80].
Other miRNAs in DM
In a recent study, miR-7 has been found to be the most
downregulated miRNAs in DM skin. The serum level of
miR-7 found a specifically decreased expression in patients
with DM compared with normal subjects or SLE and SSc,
suggesting a possibility of serum miR-7 level to be used as
a diagnostic marker for DM. They further found that the
decreased miR-7 expression in the infiltrated lymphocyte
or fibroblasts of DM skin may result in an increased
production of inflammatory molecules, leading to the skin
inflammation [81]. In addition, other group also found the
decreased expression of miR-126 in the muscle and blood
Ó 2014 John Wiley & Sons Ltd
microRNAs in autoimmune skin diseases 161
of untreated juvenile DM upregulated the expression of
vascular cell adhesion molecule 1 (VCAM-1) by TNF-a,
which suggests that VCAM-1 plays a critical role in the
pathophysiology of juvenile DM [82]. Further studies are
needed to detect new targets of these miRNA in patients
with DM.
MiRNAs and Behcet’s disease
Behcet’s disease (BD) is a recurrent systemic inflammatory
autoimmune disorder of unknown aetiology that is char-
acterized by oral aphthous ulcers, ocular lesions, genital
ulcers and skin lesions. As review by Pineton de Chambrun
et al. [83], cdT cells, cytotoxic T cells, Th1 cells, Treg cells
and Th17 cells are involved in the immunopathogenesis of
BD [83].
Recently, one research group demonstrated that an
upregulated expression of miR-142-5p and miR-21 and a
downregulated expression of miR-182 are associated with
an increased IL-17 expression in experimental autoimmune
uveoretinitis [84]. A miR-146a variant, rs2910164, was
identified to be strongly associated with BD in a Chinese
population. Expression of miR-146a was downregulated,
and certain pro-inflammatory cytokines in individuals carry
the rs2910164 CC genotype [85]. Moreover, the miR-155
expression level was decreased in PBMCs and DCs from
BD patients with active uveitis compared to controls.
Overexpression of miR-155 in DCs promoted the produc-
tion of IL-10 and inhibited the expression of IL-6 and IL-
1b. Transfected mimics of miR-155 in DCs significantly
inhibited intracellular IL-17 expression in allogeneic CD4+
T cells. However, it did not influence the expression of cell
surface markers CD80, CD40, CD83, CD86 and HLA-DR.
Luciferase reporter assays revealed that TAB 2 (TGF-b-
activated kinase 1 binding protein 2) is a target for miR-
155, which was confirmed by Western blotting [86]
(Table 1). Numerous miRNA studies on BD mechanisms
are ongoing.
MiRNAs as potential biomarkers in autoimmune
diseases with skin involvement
MicroRNAs are attractive as potential biomarkers for the
diagnosis, prognosis, disease activity and severity of
various diseases. The expression pattern of miRNAs
reflects the underlying pathophysiological processes that
are specific to various disease states. Moreover, miRNAs
can be detected in various sources, including tissue
samples, blood components and body fluids [87]. MiR-
NAs are reasonably stable and appear to be resistant to
procedures in sample handling (i.e. miRNAs can be
isolated and evaluated from formalin-fixed paraffin-
embedded samples), which increases their appeal as
practical biomarkers. The clinical utility of miRNAs as
diagnostic or prognostic biomarkers has been demon-
162 microRNAs in autoimmune skin diseases X. Deng et al.
..................................................................................................................................................................

Table 2 MiRNAs as potential biomarks in autoimmune skin diseases..

Diseases Serum miRNAs Expression levels Effects Refs

SLE MiR-146a ↓ Inversely correlation with the SLEDAI and eGFR [89]
MiR-155 ↓ Correlation with eGFR [89]
MiR-200a ↓ Inversely correlation with the SLEDAI and proteinuria [88]
MiR-342-3p, MiR-223, ↓ Correlation with active nephritis [90]
and MiR-20a
MiR-142-3p ↓ Correlation with the SLEDAI [90]
MiR-126 ↑ Potential diagnosis biomarker of SLE [91]
PS MiR-369-3p ↑ Positive linear relation with PASI scores [51]
SSc MiR-29a ↓ Higher right ventricular systolic pressure [92]
MiR-196a ↓ Higher ratio of dSSc:lSSc, higher modified Rodnan total skin [72]
thickness score and higher prevalence of pitting scars
MiR-92a ↑ Lower frequency of telangiectasia [74]
MiR-150 ↓ More severe clinical manifestations [76]
DM MiR-7,223 ↓ Relation with clinical manifestation of DM [80, 81]

SLE, Systemic lupus erythematosus; PS, psoriasis; SSc, systemic sclerosis; DM, dermatomyositis; ↑, increased; ↓, decreased; SLEDAI, SLE Disease Activity
Index; eGFR, estimated glomerular filtration rate; Refs, References; PASI scores, psoriasis activity severe index (PASI) scores; dSSc, diffuse cutaneous
scleroderma; lSSc, limited cutaneous scleroderma.

strated in various malignant and a few non-malignant
diseases [87]. There is accumulating evidence that
miRNAs play an important role in autoimmune diseases,
and various diseases or different stages of the same disease
are associated with distinct miRNA expression profiles.
Levels of urinary miR-200a, miR-200c, miR-141, miR-
429 and miR-192, and serum miR-200a, miR-200b, miR-
200c, miR-429, miR-205 and miR-192 of patients with
SLE were lower than those of controls. Estimated glomer-
ular filtration rate (eGFR) correlated with serum miR-
200b, miR-200c, miR-429, miR-205 and miR-192, while
proteinuria inversely correlated with serum miR-200a and
miR-200c [88]. Serum miR-200a inversely correlated with
SLEDAI [88]. Serum miR-146a and miR-155 levels were
lower in patients with SLE compared to controls, and the
urinary level of miR-146a was higher [89]. Serum miR-
146a inversely correlated with SLEDAI, while eGFR
correlated with serum miR-146a and miR-155 [89]. Levels
of miR-142-3p and miR-181a in plasma from patients
with SLE were increased than those of controls, and levels
of miR-106a, miR-17, miR-20a, miR-203 and miR-92a in
plasma were decreased. But there is no significant corre-
lation between these miRNAs and SLE clinical manifes-
tation. The expression of miR-342-3p, miR-223 and miR-
20a was significantly decreased in SLE patients with active
nephritis than those without active nephritis. However,
when analysing the consecutive data as a whole, this group
did observe a correlation between the SLEDAI score and
decreased expression of miR-142-3p and increased expres-
sion of miR-181b [90]. Plasma miR-126 levels are
specifically higher in patients with SLE compared to both
the healthy controls and the patients with rheumatoid
arthritis, indicating that miR-126 may be attractive
candidate as a potential diagnosis biomarker of SLE [91]
(Table 2).
Systemic sclerosis patients with lower serum miR-196a
levels had a significantly higher ratio of dSSc:lSSc, higher
modified Rodnan total skin thickness score and higher
prevalence of pitting scars than patients without lower
miR-196a levels [72]. Serum miR-29a level was not
decreased in SSc, and there was no statistically significant
difference between patients with SSc and healthy controls.
However, SSc patients with lower miR-29a levels had
significantly higher right ventricular systolic pressure than
patients with normal miR-29a levels [92] (Table 1).
Although many miRNAs in autoimmune skin diseases
have been detected as candidate biomarkers, the sensitivity
and specificity of miRNAs need to be further investigated.
And other more specific circulating miRNAs still need to
be detected.
Conclusion and perspectives
The data to date show that miRNAs play a crucial role in
the regulation of physiological and pathological processes,
and some of these miRNAs have been proven to be
associated with distinct clinical characteristics, such as
diagnosis or disease activity, which makes these miRNAs
interesting candidates for further evaluation and testing in
larger studies specifically designed to validate them as
biomarkers. Also miRNA-based gene therapies targeting
dysregulated miRNAs have the potential to become
therapeutic tools. Specific inhibition of a miRNA or the
addition of a miRNA mimics may result in a complex set
of gene expression changes in vivo or in vitro experiments.
To date, effective targeted treatments for these autoim-
mune diseases are lacking, but miRNA-based therapies in
other diseases have been under progress. For example, one
of the most successful miRNA-based therapeutic applica-
tions is the systemic administration of the miR-122

Scandinavian Journal of Immunology, 2015, 81, 153–165

X. Deng et al.
..................................................................................................................................................................
antagonist, SPC3649. This agent, which is in phase 2
clinical trials, is delivered to hepatocytes to block hepatitis
C virus replication [93]. However, further studies are
required to identify feasible targets and precise functions of
miRNAs before clinical use. MiRNAs have potential to
serve as a tool for disease diagnosis, prognosis and therapy
in the future.
Acknowledgment
This work was supported by the National Natural Science
Foundation of China (No. 81371743 and No. 81270024),
the National Basic Research Program of China (973 Plan)
(2009CB825605), the Programs of Science-Technology
Commission of Hunan province (2010FJ6032 and
2011FJ3254), the Fundamental Research Funds for the
Central Universities, and the National Key Clinical Speci-
ality Construction Project of National health and Family
Planning Commission of the People’s Republic of China.
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