Abstract
The role of microRNAs (miRNAs) during keratinocyte (KC) differentiation and in skin diseases with epidermal phenotypes has attracted strong interest over the past few years. However, combined mRNA and miRNA expression analyses to elucidate the intricate mRNA–miRNA networks of KCs at different stages of differentiation have not been performed yet. In the present study, we investigated the dynamics of miRNA and mRNA expression during KC differentiation in vitro and in normal and psoriatic epidermis. While we identified comparable numbers of up- and downregulated mRNAs (49% and 51%, respectively), miRNAs were predominantly upregulated (76% vs 24%) during KC differentiation. Further bioinformatics analyses suggested an important inhibitory role for miR-155 in KC differentiation, as it was repressed during KC differentiation in normal skin but strongly upregulated in the epidermis of psoriatic skin lesions. Mimicking the inflammatory milieu of psoriatic skin in vitro, we could show that the pro-inflammatory cytokines IL17, IL1β and INFγ synergistically upregulated miR-155 expression in KCs. Forced over-expression of miR-155 in human in vitro skin models specifically reduced the expression of loricrin (LOR) in KCs, indicating that miR-155 interferes with the establishment of a normal epidermal barrier. Together, our data indicate that downregulation of miR-155 during KC differentiation is a crucial step for epidermal barrier formation. Furthermore, its strong upregulation in psoriatic lesions suggests a contributing role of miR-155 in the altered keratinocyte differentiation observed in psoriasis. Therefore, miR-155 represents as a potential target for treating psoriatic skin lesions.
Highlights
The epidermis is a complex tissue, mainly consisting of keratinocytes (KCs) that are constantly undergoing self-renewing, differentiation and regression processes [1,2]
MiRNA/mRNA interaction networks in healthy and inflamed skin have been described before [19,32,33], little is known about the specific role of miRNAs in epidermal KC differentiation and their contribution to the epidermal phenotype of psoriasis
The vast majority of miRNAs upregulated during KC differentiation target genes involved in KC proliferation, further corroborating the assumption that these miRNAs contribute to early KC differentiation by interfering with KC proliferation
Summary
The epidermis is a complex tissue, mainly consisting of keratinocytes (KCs) that are constantly undergoing self-renewing, differentiation and regression processes [1,2]. Molecular mechanisms orchestrating epidermal KC differentiation have been extensively investigated over the past decades [6], leading to the identification of complex regulatory networks, involving mRNAs, miRNA, long non-coding RNAs and other epigenetic mechanisms of gene regulation [7,8,9,10]. These studies have built a basis for more sophisticated in silico methods to identify novel regulators based on subtle alterations in gene expression [11]. The contribution of miRNAs to the epidermal abnormalities observed in these diseases is still poorly understood [15,17]
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