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Abstract
Psoriatic skin differs distinctly from normal skin by its thickened epidermis. Most gene expression comparisons utilize full-thickness biopsies, with substantial amount of dermis. We assayed the transcriptomes of normal, lesional, and non-lesional psoriatic epidermis, sampled as split-thickness skin grafts, with 5′-end RNA sequencing. We found that psoriatic epidermis contains more mRNA per total RNA than controls, and took this into account in the bioinformatic analysis. The approach highlighted innate immunity-related pathways in psoriasis, including NOD-like receptor (NLR) signaling and inflammasome activation. We demonstrated that the NLR signaling genes NOD2, PYCARD, CARD6, and IFI16 are upregulated in psoriatic epidermis, and strengthened these findings by protein expression. Interestingly, PYCARD, the key component of the inflammasome, showed an altered expression pattern in the lesional epidermis. The profiling of non-lesional skin highlighted PSORS4 and mitochondrially encoded transcripts, suggesting that their gene expression is altered already before the development of lesions. Our data suggest that all components needed for the active inflammasome are present in the keratinocytes of psoriatic skin. The characterization of inflammasome pathways provides further opportunities for therapy. Complementing previous transcriptome studies, our approach gives deeper insight into the gene regulation in psoriatic epidermis.
Highlights
Type and severity small plaque, moderate plaque, severe plaque, guttate, moderate plaque, moderate plaque, guttate, severe plaque, moderate proinflammatory cytokines[1]
RNA sequencing (RNAseq) of psoriatic skin grafts identified a substantial number of differentially expressed transcripts
We estimated the dissimilarity between the samples by principal component analysis (PCA) (Fig. 1a), which illustrates significant overlap of the healthy skin samples (PN and C) but separation from the lesional samples
Summary
Type and severity small plaque, moderate plaque, severe plaque, guttate, moderate plaque, moderate plaque, guttate, severe plaque, moderate proinflammatory cytokines (interleukin-1 and TNF-α )[1] They recognize pathogens and endogenous cellular stress signals via pattern recognition receptors (PRRs): e.g., NOD-like (NLR) and RIG-like receptors (RLR), and mediate immune responses[5]. Several microarray studies of the psoriatic lesional skin have revealed a large number of differentially expressed genes (DEGs) in comparisons with control and non-lesional skin[6,7]. RNA sequencing (RNAseq) has provided a new alternative to microarrays; so far, two RNAseq studies on psoriasis have been published[8,9]. Our results show the power of RNAseq over the microarray studies, providing a more comprehensive view of altered signaling pathways both in non-lesional and lesional psoriatic skin. The sensitivity of the RNAseq method, together with the skin graft samples, allows a more in-depth identification of altered components in each pathway, making it possible to get a better overall understanding about affected pathways and networks in psoriatic epidermis
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