MicroRNAs in atopic dermatitis: A systematic review

Abstract Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, affecting up to 10% to 20% of children and 3% of adults. Although allergen sensitization, skin barrier abnormalities and type 2 immune responses are involved, the exact molecular pathogenesis of AD remains unclear. MicroRNAs (miRNAs) are short (19‐25 nucleotides) single‐stranded RNA molecules that regulate gene expression at post‐transcriptional level and are implicated in the pathogenesis of many inflammatory and immunological skin disorders. This systematic review sought to summarize our current understanding regarding the role of miRNAs in AD development. We searched articles indexed in PubMed (MEDLINE) and Web of Science databases using Medical Subject Heading (MeSH) or Title/Abstract words (‘microRNA/miRNA’ and ‘atopic dermatitis/eczema’) from inception through January 2020. Observational studies revealed dysregulation of miRNAs, including miR‐143, miR‐146a, miR‐151a, miR‐155 and miR‐223, in AD patients. Experimental studies confirmed their functions in regulating keratinocyte proliferation/apoptosis, cytokine signalling and nuclear factor‐κB‐dependent inflammatory responses, together with T helper 17 and regulatory T cell activities. Altogether, this systematic review brings together contemporary findings on how deregulation of miRNAs contributes to AD.

MiRNAs cannot be translated into proteins but can regulate expression of target genes post-transcriptionally. Through base-pairing between the seed region (nucleotide positions 2-8) of miRNA and its target mRNAs, miRNA could guide the RNA-induced silencing complex to their targets to induce their degradation and/or inhibit their translation.6 Altered expression of miRNAs has been documented in many kinds of diseases, including inflammatory and immunological skin disorders, which opened a novel area for researchers to understand pathogenesis, develop novel biomarkers and devise mechanism-driven therapeutic strategies.7 Recent findings have demonstrated that miRNAs play a significant role in the pathogenesis of AD.
In this systematic review, we summarize current publications concerning the role of miRNAs in the development of AD. In addition, we discuss the potential use of miRNAs as diagnostic biomarkers and therapeutic targets in AD.

| Searching strategy and selection of studies
We searched articles indexed in PubMed (MEDLINE) and Web of Science databases using Medical Subject Heading (MeSH) or Title/Abstract words ('microRNA/miRNA' and 'atopic dermatitis/ eczema') from inception through 9th January 2020. Although there was no initial limitation imposed on language during the search, only English-based literature and non-English studies with available English abstracts were further considered. We included any original study in which the role of miRNAs in AD was examined in relation to pathogenesis, diagnosis, prognosis and treatment with meeting abstracts and reviews excluded. The searching process was conducted independently by two investigators. Experts in the field of miRNAs or dermatology were involved in the literature analysis.

| Ethical review
The present study is a systemic literature review. We do not involve human beings or experimental subjects in this study, and no any identifiable private information is collected.

| RE SULTS
A total of 73 items from PubMed and 117 items from Web of Science were found based on the search criteria, among which 25 original studies investigating miRNAs in AD were finally included in this systematic review. The papers excluded were either conference abstracts, not original articles, not directly related to AD, or lacking in evidence of dysregulation of the studied miRNA(s) in human AD patients ( Figure 1). Lv et al conducted genome-wide miRNA profiling with serum and   urine samples from AD patients.8 As compared with healthy children, serum levels of miR-203 and miR-483-5p were significantly increased whereas urine miR-203 level was markedly decreased in children with AD. Increased serum miR-203 level was significantly associated with increased soluble tumour necrosis factor receptor I (sTNFRI) and sTNFRII, both of which are inflammatory markers.

| MiRNA profiles in AD
Moreover, reduced miR-203 level in urine was significantly associated with abnormal serum IgE levels in AD patients.8 By RNA sequencing using plasma samples followed by validation with reverse transcription-quantitative PCR, a recent study found that the circulating levels of miR-194-5p and miR-184 were markedly reduced whereas let-7d-5p level was increased in children with AD.9 MiR-146a and miR-125b were also reported to show significantly higher and lower levels, respectively, in the serum of AD patients as compared with the control group.10,11 Aside from normal blood samples, efforts have been made to profile miRNAs in umbilical cord serum from infants with subsequent diagnosis of AD. In this connection, increased miR-144-3p level in umbilical cord serum was associ- MiRNAs are abundant in mammalian milk and may influence the risk of AD in infants. By small RNA sequencing, Simpson et al reported that differential abundance of several miRNAs, including miR-146b-5p, miR-21-5p, miR-22-3p, miR-375 and let-7f-5p, in breast milk was associated with AD development by 2 years of age.
Nevertheless, none of these miRNAs remained significant after correction for multiple testing.17

| MiR-10a-5p
Vaher et al reported that miR-10a-5p was up-regulated in both nonlesional and lesional skin of patients with AD as compared to healthy control skin.20 Transfection of miR-10a-5p into human primary keratinocytes reduced the number of cells in S-phase and attenuated the induction of genes by IL-1β related to cell cycle regulation, cell adhesion and cytokine signalling. HAS3, a damage-associated positive regulator of keratinocyte proliferation and migration, was identified as the direct target of miR-10a-5p.20 These evidence collectively suggested that the aberrant up-regulation of miR-10a-5p in AD could impair keratinocyte proliferation that is important for maintaining the skin barrier function.

| MiR-29b
Gu et al demonstrated that miR-29b was up-regulated in lesional skin and sera from AD patients as compared with healthy individuals.14 Importantly, serum level of miR-29b was correlated with the SCORAD value (a clinical score for assessing the extent and severity of AD). Functionally, miR-29b mediated interferon (IFN)-γ-induced keratinocyte apoptosis by targeting Bcl-2-like protein 2 (BCL2L2),14 suggesting that aberrant up-regulation of miR-29b might contribute to AD-associated epithelial barrier dysfunction.

| MiR-124
Previous studies showed that miR-124 was involved in inflammatory reaction. In addition, it was demonstrated to directly target nu-

| MiR-146a
Previous studies showed that miR-146a was an anti-inflammatory miRNA with a compensatory up-regulation in psoriasis. 13

| MiR-155
MiR-155 is implicated in the regulation of innate and adaptive immune responses. In particular, miR-155 is necessary for the differen-

| MiR-223
MiR-223 expression is predominantly found in neutrophils, monocytes and eosinophils and is associated with tobacco smoking.38,39   Figure 2). Nevertheless, the functions of many AD-associated miRNAs remain obscured. Further studies are needed to systemically assess the involvement of these miRNAs in AD pathogenesis.

CO N FLI C T O F I NTE R E S T
The authors declare no competing financial interests.

AUTH O R CO NTR I B UTI O N S
Xin Yu, Meifang Wang, Linfeng Li, Matthew TV Chan and William KK Wu contributed to research conception, designed the study and wrote the manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The authors confirm that they have included a citation for available data in their references section.