Integrative Analysis of lncRNAs, miRNAs, and mRNA-Associated ceRNA Network in an Atopic Dermatitis Recurrence Model

Abstract

Atopic dermatitis (AD) is a prevalent inflammatory skin disease characterized by its chronic nature and relapse. Ample evidence suggests that non-coding RNAs play a major role in AD pathogenesis. However, the mechanism remains unknown, particularly in AD recurrence. Dynamic morphological and cytokine changes were measured throughout the whole course of an FITC-induced AD recurrence murine model. Microarray assay and integrative analysis were performed to comprehensively explore long non-coding RNA (lncRNA), messenger RNA (mRNA), and microRNA (miRNA) networks. Our results showed that an AD recurrence model was established. Overall, 5766 lncRNAs, 4025 mRNAs, and 202 miRNAs changed after elicitation, whereas, 419 lncRNAs, 349 mRNAs, and more notably, only 23 miRNAs, were dysregulated in the remission phase. Gene ontology (GO) and KEGG pathway enrichment analyses were used to investigate the potential functions of the dysregulated genes. The altered regulation of seven miRNAs and seven lncRNAs were validated in different stages of the model. The competing endogenous RNA (ceRNA) network inferred that lncRNA humanlincRNA0490+ could compete for miR-155-5p binding, through which it might affect Pkiα expression. Altogether, our findings have provided a novel perspective on the potential roles of non-coding RNAs in AD, and suggest that specific non-coding RNAs could be new therapeutic targets against AD recurrence.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…Similar results were found in comparing skin and scalp psoriasis [134]. The phenotypically severe psoriasis form generalized psoriasis pustulosa (GPP) exhibited a strong granulocyte chemotactic transcriptome reflecting the disease's histological findings (e.g., subcorneal neutrophilic pustules and neutrophilic spongiosis) [135]. Marrakchi et al, presented the role of IL36RN mutation in a case of hereditary GPP and suggested a strong role of IL-1β and IL-36 in the disease pathophysiology [136].…”

“…Additionally, the IL-1R antagonist anakinra shows frequently incomplete treatment response and IL-36 may be a more promising druggable target. However, despite GPP-specific features and susceptibility factors (e.g., CARD14 and AP1S3) [135], IL17 mRNA is also constantly present in pustular lesions. In line with this, unsupervised clustering revealed an overlap between plaque psoriasis and GPP.…”

Apremilast Normalizes Gene Expression of Inflammatory Mediators in Human Keratinocytes and Reduces Antigen-Induced Atopic Dermatitis in Mice

“…There are multiple models of AD in the mouse, using various antigens such as fluorescein isothiocyanate (FITC) [32] and dinitrochlorobenzene (DNCB) [33]. These models rely on a sensitization period wherein the antigen is applied directly to the skin of the abdomen or flank to allow dendritic cells to process and present the antigen to reactive T cells, which clonally expand and produce Th2 and Th17 cytokines and chemokines.…”

“…The immune response can be gauged by measuring the ear thickness using calipers, and by isolating proteins from ear tissue homogenate to measure cytokine and chemokine levels. For example, the FITC model is characterized by elevated expression of IL-1β, IL-4, IL-5, IL-6, IL-13, IL-17, eotaxin, monocyte chemoattractant protein (MCP)-1/chemokine (C-C motif) ligand (CCL)-2, macrophage inflammatory protein (MIP)-1α/CCL4, RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), and thymus and activation-regulated chemokine (TARC) in the ear tissue [32]. AD therapeutics have been successfully tested in these models.…”

“…The goals of these studies were to (a) assess the expression of PDE4 isoforms in the epidermis of healthy subjects and patients with AD; (b) determine the direct effects of PDE4 inhibition on Th2 (IL-4)-and Th17 (IL-17)-induced gene expression in primary adult human epidermal keratinocytes (HEKa); and (c) assess the effects of apremilast in two mouse models of AD using two antigens, FITC [32] and DNCB [33].…”