Novel Factors in the Pathogenesis of Psoriasis and Potential Drug Candidates Are Found with Systems Biology Approach

Abstract

Psoriasis is a multifactorial inflammatory skin disease characterized by increased proliferation of keratinocytes, activation of immune cells and susceptibility to metabolic syndrome. Systems biology approach makes it possible to reveal novel important factors in the pathogenesis of the disease. Protein-protein, protein-DNA, merged (containing both protein-protein and protein-DNA interactions) and chemical-protein interaction networks were constructed consisting of differentially expressed genes (DEG) between lesional and non-lesional skin samples of psoriatic patients and/or the encoded proteins. DEGs were determined by microarray meta-analysis using MetaOMICS package. We used STRING for protein-protein, CisRED for protein-DNA and STITCH for chemical-protein interaction network construction. General network-, cluster- and motif-analysis were carried out in each network. Many DEG-coded proteins (CCNA2, FYN, PIK3R1, CTGF, F3) and transcription factors (AR, TFDP1, MEF2A, MECOM) were identified as central nodes, suggesting their potential role in psoriasis pathogenesis. CCNA2, TFDP1 and MECOM might play role in the hyperproliferation of keratinocytes, whereas FYN may be involved in the disturbed immunity in psoriasis. AR can be an important link between inflammation and insulin resistance, while MEF2A has role in insulin signaling. A controller sub-network was constructed from interlinked positive feedback loops that with the capability to maintain psoriatic lesional phenotype. Analysis of chemical-protein interaction networks detected 34 drugs with previously confirmed disease-modifying effects, 23 drugs with some experimental evidences, and 21 drugs with case reports suggesting their positive or negative effects. In addition, 99 unpublished drug candidates were also found, that might serve future treatments for psoriasis.

Splicing factors differentially expressed in psoriasis alter mRNA maturation of disease-associated EDA+ fibronectin

“…fibronectin have been implicated in psoriasis pathogenesis. Application of large-scale gene expression studies extended our knowledge regarding molecular abnormalities in involved and non-involved epidermis [14][15][16][17][18][19]. Recent RNA-Sequencing-based experiments have indicated that a large number of mRNAs are consistently differentially expressed in healthy and involved skin samples across independent studies, at both the transcript and gene levels [20,21].…”

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

“…Concerning the role of associated metabolic diseases, Manczinger and Kèmeny used such a network based on a protein-protein interaction databank (STING) and chemical interaction databank (STITCH). Although further experimental validation is needed, they revealed a role of PI3KR1 in the psoriasis interaction network [29]. This protein was previously shown to play a role in insulin resistance [30] adding further evidence to the observed differential metabolic disease pathways in psoriasis.…”

“…Assessing the network of expressed transcription factors may provide information about the cellular infiltrate and the respective polarization (e.g., Th1-T-bet) [24,45]. Network construction can also be used to expose protein-protein interactions or to predict a potential drug effect based on publicly available datasets as described by Manczinger and Kèmeny [29] and others [44,46]. Ultimately, to gain biologically relevant insights via high-throughput methods, considering genomic information in the course of the data analysis is indispensable and reveals relevant DNA motifs/"psoriasis responsive elements".…”

Synthesis and activity of the salicylic acid ester of bakuchiol in psoriasis-surrogate keratinocytes and skin substitutes

“…Likewise, in skin substitutes, cytokine-induced gene expression modulation is in agreement with induction of psoriasis-like changes (increase in DEFB4A, CXCL3 and IL-8, and decrease in HPGD). In addition, there were increases in markers of psoriatic epithelium (HAS3, SERPINB1, CTGF [23][24][25] ) and decreases in markers of epithelial differentiation (KRT10, FLG). In the psoriasiform skin substitutes, bakusylan lowered the expression of six psoriasis-related genes, including STAT3 and the proinflammatory, irritation-related cytokines IL-8 and CXCL3, which, by contrast, were unfavourably upregulated by ATRA and adapalene (ADP) (IL-8) and tazarotene (TAZ) (CXCL3).…”