miR-155 Contributes to Normal Keratinocyte Differentiation and Is Upregulated in the Epidermis of Psoriatic Skin Lesions

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.

An In Vitro Model of Avian Skin Reveals Evolutionarily Conserved Transcriptional Regulation of Epidermal Barrier Formation

“…The keratinocyte differentiation program of chicken keratinocytes was compared to that of human keratinocytes (Affymetrix GeneChip analysis, GenBank accession number GSE145059) cultured under equivalent conditions as those described above for chicken keratinocytes (Beer et al, 2020). Like in chicken models, there was a broad upregulation of gene expression in the EDC and selective upregulation of a subset of keratin genes in human skin models (Figure S5).…”

Identification of key genes and Construction of miRNA-mRNA regulatory network in Psoriasis based on Bioinformatics Analysis

“…Previous studies have con rmed that miR-21, miR-31, miR-146a, miR-155, and miR-203 are signi cantly upregulated in skin lesions of patients with psoriasis [9] . Overexpression of miR-155 in psoriatic skin reduces loricrin expression in keratinocytes and destroys the characteristics of the epidermal barrier [10] . In vitro, using keratinocyte induced HaCaT cells as a model of psoriasis, miR-155 silencing was demonstrated to signi cantly reduce in ammation and NLRP3/ caspase-1 signaling.…”

Anton Luger Dissertationspreise der ÖGDV 2022

“…Es wurde zudem versucht, microRNAs, die für die Entwicklung der Epidermis wichtig sind, zu identifizieren 4 . miR‐155 wurde ausschließlich in basalen Keratinozyten exprimiert und war in der Psoriasis stark erhöht.…”