The role of microRNAs in autoimmune diseases with skin involvement.

Article Type : Review

The role of microRNAs in autoimmune diseases with skin involvement

Xinjie Deng1#, Yuwen Su1#, Haijing Wu1, Ruifang Wu1, Peng Zhang1, Yong Dai2, Tak-Mao Chan3, Ming Zhao1*, Qianjin Lu1*

1

Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, Hunan 410011, PR China

2

Clinical medical research center, the Second Clinical medical college of Jinan University

(Shenzhen People’s Hospital), Shenzhen, Guangdong, 518020, R.P. China 3

Division of Nephrology, Department of Medicine, University of Hong

Kong, Queen Mary Hospital, Hong Kong, China

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/sji.12261 This article is protected by copyright. All rights reserved.

*Correspondence: Ming Zhao, Qianjin Lu. Second Xiangya Hospital, Central South University, #139 Renmin Middle Road, Changsha, Hunan 410011, P.R. China. Tel.: +86-731-85295860, Fax: +86-731-85533525, E-mail address: [email protected] (M. Zhao), [email protected](Q. Lu).

#

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 3' 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 development. 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 autoimmunity are elucidated to provide information for clinical implications.

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immune complexes and self-reacting lymphocytes. Autoreactive autoantibodies (e.g., anti-dsDNA) and the deposition of complement-fixing immune complexes are prominent causes of the inflammation and damage to multiple organs in SLE patients [21].

Studies of miRNA expression profiles in SLE patients reveal the biological and clinical relevance of miRNAs in SLE. An initial effort used TaqMan microRNA 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 SLE patients 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 SLE patients[22]. In addition, in our previous study, we found that 6 miRNAs, including miR-1246, miR-574-5p, miR-1308, miR-638, miR-7, and miR-126, were up-regulated, and 5 miRNAs, including miR-142-5p, miR-142-3p, miR-31, miR-186, and miR-197, were down-regulated in CD4+ T cells from 30 Chinese lupus patients compared to 20 healthy subjects[23]. Another analysis of 365 miRNAs in PBMCs from 34 Greece lupus patients and 20 normal controls identified 14 down-regulated miRNAs and 13 up-regulated miRNAs in patients compared to controls[24]. Among these abnormally expressed miRNAs, many have been implicated to act as inhibitors of numerous mRNAs involved in the process of SLE development, suggesting that dysregulated expression of miRNAs play an important role in the pathogenesis of SLE (Table 1).

3.1.1. 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 plasmacytoid


methyltransferase (DNMT) in SLE. For example, our and others’ previous studies confirmed that the dysregulation of miR-126, and miR-148a, miR-29b in CD4+ T cells from lupus patients lead to DNA hypo-methylation via targeting DNMT[23,32,39,40]. Initially, two studies identified that miR-148a was up-regulated in CD4+ T cells from lupus individuals[32,39]. Overexpression of miR-148a in CD4+ T cells leads to DNA hypo-methylation 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 down-regulate DNMT1. Overexpressed miR-126 and miR-29b caused DNA hypo-methylation and an up-regulation of genes encoding CD11a (ITGAL) and CD70 (TNFSF7), which contributed to T cell and B cell hyper-activity[23,40].

3.2. 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 hematopoiesis (miR-142-3p)[44,45]. The abnormally up-regulated or down-regulated miRNAs levels play an important role in the mechanisms underlying psoriasis. Among these miRNAs, miR-203, miR-146a, miR-31, miR-21


psoriasis lesions by regulating the production of mediators of inflammation and/or fibrosis such as TGF-β, and leukocyte 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 psoriasis patients compared to healthy subjects. MiR-369-3p levels in skin had a positive linear relationship with psoriasis activity severe index (PASI) scores [51].

3.3. MiRNAs and Systemic sclerosis Systemic sclerosis (SSc) is a highly heterogeneous autoimmune disease that is characterized by microvascular dysfunction, progressive fibrosis of the skin and/or internal organs, and immune abnormalities[63]. As reviewed by Gabrielli A 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 predisposition and epigenetic modifications caused by environmental factors[65]. MiRNAs, as one of the epigenetic features, has been identified in skin fibroblasts and sera of SSc patients (Table 1). The aberrant expression of miRNAs is likely to be the critical factor for pro- or anti-fibrosis, 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 scleroderma (dSSc) and 60 miRNAs were altered in limited cutaneous scleroderma (lSSc). A This article is protected by copyright. All rights reserved.

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].

3.4.3. Other miRNAs in DM In a recent study, miR-7, has been found to be the most down-regulated miRNAs in DM skin. The serum level of miR-7 and 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 of untreated juvenile DM up-regulated the expression of vascular cell adhesion molecule 1 (VCAM-1) by TNF-α, 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.

3.5. MiRNAs and Behcet’s disease (BD) BD is a recurrent systemic inflammatory autoimmune disorder of unknown etiology that is characterized by oral aphthous ulcers, ocular lesions, genital ulcers, and skin lesions. As review by Pineton de Chambrun M et al [83], γδT 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 up-regulated expression of miR-142-5p and miR-21 and a down-regulated expression of miR-182 are associated with an increased IL-17 expression in experimental autoimmune uveoretinitis[84]. A miR-146a This article is protected by copyright. All rights reserved.

variant, rs2910164, was identified to be strong associated with BD in a Chinese population. Expression of miR-146a was down-regulated, 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 production of IL-10 and inhibited the expression of IL-6 and IL-1β. 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 TAB2 (TGF-β 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.

4. MiRNAs as potential biomarkers in autoimmune diseases with skin involvement MiRNAs 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]. MiRNAs 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 demonstrated in various malignant and a few nonmalignant 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 SLE patients were lower


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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].

3.1.3. MiR-21 in SLE MiR-21 has been reported to be up-regulated 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 de-repressed 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 promoted DNA hypomethylation in lupus CD4+ T cells by repressing DNA methyltransferase 1 (DNMT1) expression. Further experiments revealed that miR-21 indirectly down-regulated DNMT1 expression by targeting an important autoimmune gene, RASGRP1[32]. Plasma miR-21 level in SLE patients was higher than that of healthy controls, and significantly correlated with the level of plasma complement C3, C4, and serum uric acid in SLE patients[33].

3.1.4. 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 5' This article is protected by copyright. All rights reserved.

arm of the locus, and miR-142-3p is expressed from the 3' arm[35]. Our group revealed that miR-142-3p and miR-142-5p were significantly down-regulated in SLE CD4+ T cells compared with healthy controls. MiR-142-3p targets members of the signaling lymphocytic activation molecule (SLAM) family, interleukin-10 (IL-10) and CD84, and miR-142-5p targets SLAM-associated protein (SAP) by interacting with their 3'-UTR. Down-regulation 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, 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 up-regulated H3K27 tri-methylation and DNA methylation within the regulatory region 500 bp upstream of the miR-142 precursor sequence[36].

3.1.5. MiR-125a in SLE MiR-125a is involved in one of the inflammatory chemokine pathways in autoimmune disease that has been proposed in the pathogenesis of lupus. MiR-125a negatively 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.

3.1.6. Other miRNAs in SLE MiRNAs, as one of the major epigenetic features, interlink DNA methylation and histone modifications[36], target certain genes and regulate related pathways. Currently，many studies have showed that miRNAs regulates DNA methylation by targeting the DNA This article is protected by copyright. All rights reserved.

varepsilon, VCAM-1: vascular cell adhesion molecule 1, DCs: dendritic cells, TAB2: TGF-β activated kinase 1 binding protein 2, Refs：References

Table 2: MiRNAs as potential biomarks in autoimmune skin diseases Diseases

SLE

Serum

Expression

miRNAs

levels

MiR-146a

↓

Effects

Refs

Inversely correlation with the

[89]

SLEDAI and eGFR

MiR-155

↓

Correlation with eGFR

[89]

MiR-200a

↓


[88]

SLEDAI and proteinuria

MiR-342-3p,

↓

Correlation with active nephritis

[90]

MiR-142-3p

↓

Correlation with the SLEDAI

[90]

MiR-126

↑

Potential diagnosis biomarker of

[91]

MiR-223, and MiR-20a

SLE PS

MiR-369-3p

↑

Positive linear relation with PASI

[51]

scores SSc

MiR-29a

↓

Higher right ventricular systolic pressure


[92]

MiR-196a

↓

Higher ratio of dSSc:lSSc, higher

[72]

modified Rodnan total skin thickness score, and higher prevalence of pitting scars MiR-92a

↑

Lower frequency of telangiectasia

[74]

MiR-150

↓

More severe clinical

[76]

manifestations DM

MiR-7,223

↓

Relation with clinical

[80,81]

manifisitation of DM

Abbreviations: SLE: Systemic lupus erythematosus, Psoriasis: PS, 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


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-α and IL-1β, also target miR-146a expression[58]. TNF-α is an important mediator in leukocyte-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.

3.2.3. MiR-21 in psoriasis Besides SLE, miR-21 is also involved in the pathogenesis of psoriasis. MiR-21 has been found to be up-regulated in dermal T cells and epidermal cells of psoriasis patients, 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. Tumor 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 pathway is a general feature in tumors 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 (tumor necrosis factor–α–converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 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].


3.2.4. MiR-125b in psoriasis Another research group identified that miR-125b in skin lesions of psoriasis patients played an important role in the regulation of keratinocyte proliferation and differentiation, 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 hyper-proliferation and aberrant differentiation of keratinocytes[52]. Furthermore, miR-125b also targets TNF-α, which suggests that its down-regulation in response to LPS may be required for proper TNF-α production and for miR-125b to play a role in innate immune response[45,62].

3.2.5. 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 over expressed in keratinocytes from psoriasis patients. Furthermore, interference with endogenous miR-31 decreased the ability of keratinocytes to activate endothelial cells and attract leukocytes. Serine/threonine kinase 40 (STK40), which is a negative regulator of NF-κB signaling, is a direct target of miR-31. MiR-31 regulates cytokine/chemokine expression via the targeting of STK40 in keratinocytes. Moreover, overexpression of miR-31 contributes to skin inflammation in


psoriasis lesions by regulating the production of mediators of inflammation and/or fibrosis such as TGF-β, and leukocyte 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 psoriasis patients compared to healthy subjects. MiR-369-3p levels in skin had a positive linear relationship with psoriasis activity severe index (PASI) scores [51].

3.3. MiRNAs and Systemic sclerosis Systemic sclerosis (SSc) is a highly heterogeneous autoimmune disease that is characterized by microvascular dysfunction, progressive fibrosis of the skin and/or internal organs, and immune abnormalities[63]. As reviewed by Gabrielli A 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 predisposition and epigenetic modifications caused by environmental factors[65]. MiRNAs, as one of the epigenetic features, has been identified in skin fibroblasts and sera of SSc patients (Table 1). The aberrant expression of miRNAs is likely to be the critical factor for pro- or anti-fibrosis, 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 scleroderma (dSSc) and 60 miRNAs were altered in limited cutaneous scleroderma (lSSc). A This article is protected by copyright. All rights reserved.

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 SSc patients, including 9 up-regulated miRNAs and 15 downregulated miRNAs, using miRNA microarray chip analysis[68]. Many of these altered miRNAs were related to pathophysiological processes of SSc and involved in autoimmune, vascular and fibrotic processes (Table 1).

3.3.1. MiR-29 in SSc MiR-29a and miR-29b, as a main part of miR-29 family, were highlighted in recent. MiR-29a exerts anti-fibrotic effects in several major fibrotic disorders, such as SSc[69]. MiR-29a is significantly reduced in fibroblasts and skin lesions from SSc patients 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 fibrogenesis and its potential application as a putative therapeutic target[70]. TGF-β, IL-4, or platelet-derived growth factor B (PDGF-B) reduced the levels of miR-29a in fibroblasts, which further up-regulated PDGF-B and TGF-β[69,70]. This positive feedback loop can lead to an uncontrolled accumulation of ECM proteins. However, inhibition of PDGF-B and TGF-β 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 up-regulation 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.

3.3.2. MiR-21 and MiR-145 in SSc Several studies have demonstrated that aberrant expression of miR-21 and miR-145 are involved in pathogenesis of SSc. MiR-21 expression was up-regulated 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 down-regulated This article is protected by copyright. All rights reserved.

protein levels of the SMAD family and their co-factors could result in heightened fibrogenesis. TGF-β, secreted by fibroblasts or myofibroblasts, plays a pivotal role in fibrosis by directly mediating fibrosis and inducing the trans-differentiation of mesenchymal cells to myofibroblasts[71]. After stimulation with TGF-β, the level of miR-21 expression was increased and the expression level of SMAD7 was decreased. TGF-β also raises miR-145 expression and reduces mRNA level of SMAD3. Both miR-21 and miR-145 may exert pro- or anti-fibrosis effects in SSc [67].

3.3.3. 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-β siRNA. Investigation of the regulatory mechanisms of type I collagen expression by miR-196a may lead to novel treatments using miRNAs[72].

3.3.4. 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 SSc. One recent study validated that miR-129-5p was down-expressed in SSc fibroblasts, and it can also be up-regulated by IL-17A expression, which reduces the expression of type I collagen and connective tissue growth factor[73]. However, miR-92a is up-regulated in sera and fibroblasts of SSc, and it down-regulates the expression of MMP-1, which is one target gene of miR-92a. The stimulation of intrinsic TGF-β 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 up-regulated in SSc dermal fibroblasts in vivo and in vitro, had an inhibitory effect on collagen expression[75]. One new study demonstrated that This article is protected by copyright. All rights reserved.

miR-150 expression is also decreased in fibroblasts and sera of SSc patients. Reduced expression of miR-150 increased type I collagen expression via the induction of integrin β3. Treatment of SSc fibroblasts with 5-AdC revealed that the miR-150 down-regulation in these cells was caused by DNA methylation[76].

The miRNAs identified above have been confirmed to have pro- or anti-fibrotic effects in SSc via different signaling pathways. Inhibiting the function of these pro-fibrotic miRNAs through the use of specific miRNA inhibitors and promoting anti-fibrotic miRNAs through gene therapy or the use of specific miRNA mimics will provide novel therapeutic options in the future.

3.4. MiRNAs and Dermatomyositis (DM) 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 K et al [78]，autoantibodies (especially anti-Jo-1, anti-Mi-2), and pro- or anti-inflammatory cytokines, have been detected in the serum of DM patients.

The etiology 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 down-regulated in DM skin (Table 1).


3.4.1. 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 DM patients [79]. They identified CD3+CD8−IL-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 differentiation, were also increased obviously in the PBMCs from DM patients. 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 DM patients. 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 DM patients.

3.4.2. MiR-223 in DM Another group explored the expression pattern of miRNAs in Gottron’s papules of DM patients 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 PKCε (protein kinase C varepsilon), one of the putative target genes of miR-223, in the hyper-proliferated epidermis of Gottron’s papules in DM patients. A specific inhibitor of miR-223 can induced cell proliferation while knockdown of PKCε by a specific siRNA can decrease cell number, demonstrating that miR-223 is involved in the keratinocyte proliferation via targeting PKCε. In this study, they also detected the serum level of miR-223 in DM patients 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, This article is protected by copyright. All rights reserved.

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].

3.4.3. Other miRNAs in DM In a recent study, miR-7, has been found to be the most down-regulated miRNAs in DM skin. The serum level of miR-7 and 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 of untreated juvenile DM up-regulated the expression of vascular cell adhesion molecule 1 (VCAM-1) by TNF-α, 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.

3.5. MiRNAs and Behcet’s disease (BD) BD is a recurrent systemic inflammatory autoimmune disorder of unknown etiology that is characterized by oral aphthous ulcers, ocular lesions, genital ulcers, and skin lesions. As review by Pineton de Chambrun M et al [83], γδT 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 up-regulated expression of miR-142-5p and miR-21 and a down-regulated expression of miR-182 are associated with an increased IL-17 expression in experimental autoimmune uveoretinitis[84]. A miR-146a This article is protected by copyright. All rights reserved.

variant, rs2910164, was identified to be strong associated with BD in a Chinese population. Expression of miR-146a was down-regulated, 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 production of IL-10 and inhibited the expression of IL-6 and IL-1β. 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 TAB2 (TGF-β 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.

4. MiRNAs as potential biomarkers in autoimmune diseases with skin involvement MiRNAs 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]. MiRNAs 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 demonstrated in various malignant and a few nonmalignant 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 SLE patients were lower


than those of controls. Estimated glomerular 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 SLE patients 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 SLE patients 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 correlation between these miRNAs and SLE clinical manifistestion. 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 analyzing 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 expression of miR-181b[90]. Plasma miR-126 levels is specifically higher in SLE patients compared to both the healthy controls and the rheumatoid arthritis patients, indicating that miR-126 may be attractive candidate as a potential diagnosis biomarker of SLE[91] (Table 2).

SSc 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 SSc patients 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).

Though 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 be detected. This article is protected by copyright. All rights reserved.

5. Conclusion and perspectives The data to date shows 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 autoimmune diseases are lacking, but miRNA-based therapies in other diseases have been under progress. For example, one of the most successful miRNA-based therapeutic applications is the systemic administration of the miR-122 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.

Acknowledgments 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 Speciality Construction Project of National health and Family Planning Commission of the People's Republic of China.


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Table 1:Aberrant miRNA expression in autoimmune skin disease

Diseas

MiRNAs

Tissues/cells

es SLE

Expressi

Targets

Effects

Refs

IRF-5

Up-regulation

[22]

on level MiR-146a

PBMC from

↓

SLE patients

STAT-1

of type I IFN expression

MiR-125a

T cells from

↓

KLF13

SLE patients

Up-regulation of RANTES expression


[37]

MiR-148a

CD4+ T cells

↑

from SLE

DNMT3B DNMT1

patients

DNA

[32]

hypo-methylati

[39]

on Up-regulation of CD70 and LFA-1 expression

MiR-155

Treg cells in

↑

MRL/lpr mice

CD62L Ets-1

Regulation of Treg cell

[18] [28]

phenotype

PBMCs from

[30] Correlation with

juvenile SLE

anti-dsDNA antibody production Correlation with SLEDAI score and proteinuria MiR-21

CD4+ T cells

↑

from MRL-lpr

PDCD4 RASGRP1

mice and SLE

Correlation with [24] SLEDAI score

[32]

DNA

patients

hypo-methylati on

MiR-126

CD4+ T cells

↑

DNMT1

from SLE patients


T cell and B cell hyper-activity DNA

[23]

demethylation

MiR-29b

CD4+ T cells

↑

SP1

DNA

from SLE

hypo-methylati

patients

on

[40]

Up-regulation of CD11a and CD70 expression MiR-142-3p/

CD4+ T cells

5p

from SLE

↓

SAP, CD84, and IL-10

T cell

[36]

over-activation and B cell

patients

hyper-stimulati on Histone modification and DNA methylation PS

MiR-203

Keratinocytes

↑

from PS patients

SOCS3,

Modulation of

[45]

TNF-α

cytokine

[54]

and IL24

expression

[56]

Enhancement of keratinocyte differentiation MiR-146a

Skin lesion

↑

IRAK1,

and PBMC of This article is protected by copyright. All rights reserved.

Correlation with [57]

PS patients

TRAF6

IL-17 expression [58]

TNF-α and

Involvement in

IL-1β

innate immune response

MiR-369-3p

Serum sampl

↑

ND

Positive linear

es

relation with

and skin tissu

PASI scores

[51]

es from PS patie nts MiR-125b

Keratinocyte

↓

from PS

TNF-α and

Modulation of

FGFR2

keratinocyte

[45] [52]

proliferation

patients

[62] and its differentiation Involvement in innate immune response MiR-31

Keratinocyte

↑

STK40

Contribution to

from PS

skin

patients

inflammation Regulation of cytokine expression Promotion of


[48]

inflammation MiR-21

T cells from PS patients

↑

ND

↑

Contribution to

[49]

skin

[60]

inflammation

Epidermal lesions of PS

Reduction

patients

epidermal

[61]

TIMP-3 expression MiR-210

SSc

MiR-21

CD4+ T cells

↑

FOXP3

Dysregulation

from PS

of Immune

patients

function

Skin samples

↑

SMAD7

and FBs from

Promotion of

[50]

[67]

fibrosis

SSc patients MiR-145

MiR-29b

Skin samples

↓

SMAD3

Up-regulation

and FBs from

of SAMD3

SSc patients

expression

Skin samples

↓

COL1A1

Up-regulation

and FBs from

of

SSc patients

COL1A1 express

[67]

[67]

ion Suppression of fibrosis MiR-92a

FBs or serum

↑

MMP-1

from SSc


Promotion of fibrosis

[74]

patients MiR-7

FBs from SSc

↑

ND

Suppression of

[75]

collagens

patients

expression MiR-29a

FBs from SSc

↓

ND

patients MiR-196a

FBs and

Suppression of

[69]

fibrosis ↓

ND

serum from

Promotion of

[66][7

fibrosis

2]

Down-regulatio

[73]

SSc patients MiR-129-5p

FBs from SSc

↓

ND

n of type I

patients

collagen expression MiR-150

FBs and

↓

ND

serum from

Suppression of

[66][7

fibrosis

6]

Enhancement

[79]

SSc patients DM

MiR-206

MiR-223

Serum and

↓

KLF

PBMCs of DM

of TH17 cells

patients

frequency

Skin lesion

↓

and serum of

PKCvarepsil

Relation with

on

clinical

DM patients

[80]


MiR-126

Muscle and

↓

ND

blood


Up-regulation of VCAM-1

[82]

samples of

expression

untreated Juvenile DM patients MiR-7

Skin lesion

↓

ND

ND

[81]

↓

ND

Association of

[85].

and serum of DM patients BD

MiR-146a

PBMCs from

rs2910164 of

BD patients

miR-146a MiR-155

PBMCs and

↓

TAB2

Modulation of

DCs from BD

cytokines

patients

expression

[86]

Abbreviations: SLE: Systemic lupus erythematosus, Psoriasis: PS, 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 : signaling lymphocytic activation molecule associated protein, IL-10: interleukin-10, SOCS-3: suppressors of cytokine signaling 3, TNF-α: tumor 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, PKCε:protein kinase C


varepsilon, VCAM-1: vascular cell adhesion molecule 1, DCs: dendritic cells, TAB2: TGF-β activated kinase 1 binding protein 2, Refs：References

Table 2: MiRNAs as potential biomarks in autoimmune skin diseases Diseases

SLE

Serum

Expression

miRNAs

levels

MiR-146a

↓

Effects

Refs


[89]

SLEDAI and eGFR

MiR-155

↓

Correlation with eGFR

[89]

MiR-200a

↓


[88]

SLEDAI and proteinuria

MiR-342-3p,

↓

Correlation with active nephritis

[90]

MiR-142-3p

↓

Correlation with the SLEDAI

[90]

MiR-126

↑

Potential diagnosis biomarker of

[91]

MiR-223, and MiR-20a

SLE PS

MiR-369-3p

↑

Positive linear relation with PASI

[51]

scores SSc

MiR-29a

↓

Higher right ventricular systolic pressure


[92]

MiR-196a

↓

Higher ratio of dSSc:lSSc, higher

[72]

modified Rodnan total skin thickness score, and higher prevalence of pitting scars MiR-92a

↑

Lower frequency of telangiectasia

[74]

MiR-150

↓

More severe clinical

[76]

manifestations DM

MiR-7,223

↓

Relation with clinical

[80,81]


Abbreviations: SLE: Systemic lupus erythematosus, Psoriasis: PS, 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


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