Abstract
Keratinocyte stress-response of the uninvolved psoriatic epidermis is known to be altered compared to healthy cells. Therefore, we aimed to reveal potential mechanisms underlying this alteration. We compared the expression of annotated cell-stress-related proteins between uninvolved psoriatic and healthy skin using the protein array method. Data were analyzed by the Reactome over-representation test. We found that p27/CDKN1B and cytochrome C showed at least a two-fold increase, while cyclooxygenase-2, indolamine-2,3-dioxygenase-1, serum paraoxonase 1, serum paraoxonase 3, serine-46-phosphorylated tumor protein p53, and superoxide-dismutase-2 showed a two-fold decrease in expression in the uninvolved skin. Over-representation analysis suggested the Forkhead-box protein O (FOXO)-mediated transcription as the most significant pathway affected by the differently expressed cell-stress-related proteins (DECSRPs). DECSRPs indicate increased FOXO-mediated transcription of cell-cycle genes and reduced interleukin-signaling in the psoriatic uninvolved skin. Nuclear positivity of the FOXO-signaling-related p27/CDKN1B and FOXO1 are negatively correlated with the disease severity and showed increased expression in the uninvolved epidermis and also in healthy primary keratinocytes, which were grown on cartilage oligomeric matrix protein-coated surfaces. Our results indicate a cell-cycle inhibitory process, as a stress-related compensatory mechanism in the uninvolved epidermis, that could be responsible for blocking keratinocyte hyperproliferation in the psoriatic uninvolved skin, thus maintaining the symptomless skin phenotype.
Highlights
Chronic plaque-type psoriasis is the most common form of the immune-mediated inflammatory skin disease, psoriasis
We found eight differentially expressed cell-stress-related proteins (DECSRPs) with two-fold changes in the psoriatic uninvolved skin compared to healthy skin
Regulation of the stress response can take place at different levels; we performed a cell-stress protein array to widely reveal regulation of the stress response in uninvolved skin compared to healthy skin at the protein level
Summary
Chronic plaque-type psoriasis is the most common form of the immune-mediated inflammatory skin disease, psoriasis. Genetic and environmental factors interplay in triggering the appearance of the characteristic red and silver scaly plaques on the skin of patients [1,2]. The pathomechanism of this multifactorial disease is not fully understood and with current therapeutic possibilities, recurrence of symptoms cannot yet be prevented [3]. It is noteworthy that in psoriasis the healthy-looking uninvolved skin has several cellular and extracellular alterations that make the skin susceptible to the development of symptoms [4]. The psoriatic uninvolved skin of patients provides tissue samples where we can search for alterations relative to healthy skin. Several studies have described incomplete basement membrane below the basal keratinocyte layer of the epidermis [5,6,7] along with altered integrin expression of basal keratinocytes [8]
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