Research paperMicroRNA-124 alleviates chronic skin inflammation in atopic eczema via suppressing innate immune responses in keratinocytes
Introduction
Eczema, a skin inflammatory reaction mediated by antigen-specific T cells [1], occurs in 15%–20% of infants and young children and persists throughout adulthood in 1%–3% of the cases [2]. The most common type of eczema is atopic eczema, in which a dry, itchy rash develops [3]. Recurrent exacerbations, activation of the immune system, and hyperplasia and keratinocyte apoptosis in the chronic phase represent cardinal features of atopic eczema [2], [4], [5].
Skin inflammation during an exacerbation can persist for several weeks and is nearly exclusively complicated with secondary infections that contribute to the activation of innate immune responses and the nuclear factor kappa B (NF-κB) pathway in keratinocytes [6], [7]. Several studies have reported that NF-κB plays a critical role in the production of chemokines in TNF-α and/or IFN-γ-stimulated keratinocytes [8], [9], [10]. IFN-γ can induce several characteristic chemokines in keratinocytes, including CCL5 (also known as RANTES) and CCL8 (also known as MCP-2) [11], [12]. CCL5 promoter polymorphisms and enhanced levels have been shown to be associated with atopic dermatitis [13], [14], [15]. CCL8 mediates the recruitment of IL-5-enriched TH2 cells in the inflamed skin in a mouse model of chronic atopic dermatitis [16]. In addition, the presence of TNF-α could increase the secretion of GM-CSF, CCL5, and IL-10 [17].
Regulation of inflammatory responses in diseases is mediated by coordinated control of gene expression, which is also modulated by microRNAs (miRNAs). MiRNAs silence genes by triggering the degradation of target mRNAs and inhibition of translation [18], [19]. Several miRNAs, including miR-124, function in the regulation of various inflammatory processes [20], [21], [22]. In glioma cells, the restoration of miR-124 can reduce the activation of NF-κB [23]. Additionally, an activated NF-κB-centered inflammatory loop in the highly aggressive non-small cell lung cancer cells leads to down-regulation of miR-124 [24]. The transfection of PC12 neurons with miR-124 counteracted the inhibition of neurites mediated by both recombinant TNF-α and macrophages, suggesting that miR-124 might be a valuable tool for desensitizing neurons to a repulsive inflammatory environment [25]. However, the function of miR-124 in the normal skin and keratinocytes and in atopic eczema has not been previously explored.
Here, we demonstrate that the level of miR-124 is decreased in lesions tissue from patients with atopic eczema and also decreased in keratinocytes in response to inflammation factors, in turn, controls chronic inflammatory processes that are triggered by TNF-α and/or IFN-γ though direct targeting NF-κB and regulation of CCL5, CCL8 and IL-8 expression in keratinocytes.
Section snippets
Tissues, cell lines and cell transfection
We collected 37 paired atopic eczema skin lesional tissues and normal non-lesional tissues with approval of the Ethical Review Committees on Hunan University of Chinese Medicine. All patients signed a written informed consent form and were diagnosed by dermatologists according to the diagnostic standard for atopic eczema. The criteria for diagnosis and disease phase of these patients were Eczema Area and Severity Index (EASI) [26].
For functional studies, pooled, normal human epidermal
MiR-124 expression was downregulated in atopic eczema tissues and in response to inflammatory factor stimulation
Previous studies have reported the association between miR-124 and inflammatory factors [25], [27]. Here we firstly evaluated miR-124 expression in atopic eczema lesional tissues and non-lesional normal tissues (n = 37). Results from real-time PCR assays showed that miR-124 expression was downregulated in atopic eczema tissues, compared to the non-lesional normal tissues (Fig. 1A). Next, we conducted a series of inflammatory factor treatment, including IL-13, IL-1β, IL-17A, IL-4, IFN-γ and TNF-α,
Discussion
Information regarding the role of miRNAs in allergic diseases is limited [30], [31]. The present study demonstrates an essential immune regulatory function of miR-124 in the inflammatory skin of atopic eczema. miR-124 is downregulated in the lesional skin of patients with atopic eczema and inhibits the expression of p65 through direct binding to the 3′UTR of RELA, thus to suppress numerous proinflammatory factors, including IFN-γ- or TNF-α- inducible genes IL-8, CCL5 and CCL8 in human primary
Acknowledgments
This work was supported by the National Natural Sciences Foundation of China (No: 81573985) and Chinese medicine research project of Hunan Province (No: 2016137 and 2016127).
Author disclosure statement
There is no conflict of interest.
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