INVESTIGATIVE REPORT
441 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Overexpression of Psoriasin( S100A7) Contributes to Dysregulated Differentiation in Psoriasis
Anna-Karin EKMAN, Jenny VEGFORS, Cecilia BIVIK EDING and Charlotta ENERBÄCK Ingrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.
Key words: psoriasin; S100A7; differentiation; keratinocyte; psoriasis.
Accepted Dec 12, 2016; Epub ahead of print Dec 13, 2016 Acta Derm Venereol 2017; 97: 441 – 448.
Corr: Charlotta Enerbäck, Ingrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden. E-mail: charlotta. enerback @ liu. se
To establish the skin barrier and the epidermal structure, keratinocytes undergo a tightly regulated process of differentiation. In this process, the keratinocytes progress from the basal layer of the epidermis through distinct stages to form the spinous, granular and cornified layers. Each of these layers is characterized by specific features in terms of gene expression, function and cellular morphology( 1).
In psoriasis, the differentiation process of the epidermal cells is disturbed. The keratinocytes in active psoriatic lesions display an altered sequence and altered expression levels of the differentiation markers( 2). However, the mediators that are responsible for the dysregulated differentiation of psoriatic keratinocytes have not been identified.
Psoriasin( S100A7) was first identified for its overexpression in psoriatic keratinocytes( 3), where it was found to be located to the nucleus and the cytoplasm( 4). Later studies have demonstrated secretion of psoriasin from epithelial cells( 5). Intracellular psoriasin has been found to interact with various signalling proteins, including the nuclear factor( NF)-kB regulator Jab1, while secreted psoriasin functions as an antimicrobial peptide and has the ability to induce chemotaxis of neutrophils and T cells( 6). Psoriasin is strongly induced by interleukin( IL)-22 and by the combination of IL-17 and tumour necrosis factor( TNF)-α, which emphasizes the role of psoriasin in the pathogenesis of psoriasis( 7). We have shown previously that extracellular psoriasin binds to the receptor for advanced glycation end products( RAGE), promoting endothelial cell proliferation( 8). In addition to the low expression in normal skin and the high expression in the psoriatic epidermis, psoriasin is also expressed in conditions displaying abnormal differentiation. In a spectrum of conditions of dysregulated keratinocyte differentiation, we have previously demonstrated strong psoriasin expression in differentiated squamous cell carcinoma and a lack of expression in undifferentiated basalioma( 9). This pattern of expression suggests an involvement in epithelial differentiation. In addition, the gene that encodes psoriasin is positioned within the epidermal differentiation complex( EDC)( 10 – 12), a gene cluster that contains several genes of importance in the terminal differentiation of the human epidermis( 10, 11).
The high expression level in psoriatic epidermis in conjunction with the disturbed differentiation process suggests that psoriasin is involved in keratinocyte differentiation. Previous studies of the role of psoriasin in keratinocyte differentiation have focused on the effects of extracellular psoriasin, but as the psoriasin in psoriasis is keratinocyte-derived, it is imperative to consider the effects of psoriasin as an endogenously produced intracellular mediator. The aim of this study was therefore to investigate the effect of keratinocyte-derived, intracellular psoriasin on keratinocyte differentiation.
METHODS Cells and culture conditions
Neonatal human epidermal keratinocytes( HEKn; Life Technologies, Carlsbad, CA, USA), were cultured in EpiLife medium supplemented with 1 % EpiLife defined growth supplement( EDGS), 0.06 μM CaCl 2
( Gibco, Paisley, UK) and 1 % penicillin / streptomycin( PAA Laboratories, Pasching, Austria). The keratinocyte cell line NTERT-2G was grown in keratinocyte serum-free medium( KFSM, Gibco) as described previously( 13). Extracellular treat-
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2596 Acta Derm Venereol 2017; 97: 441 – 448