94 An investigation of the molecular pathogenesis of Generalized Pustular Psoriasis through neutrophil RNAseq

摘要

Psoriasis is a complex skin disorder that has been classified into several forms, including common plaque psoriasis (Ps), a T-cell mediated disease, and Generalised Pustular Psoriasis (GPP), a rare condition associated with systemic neutrophilic inflammation. While the genetic basis of Ps has been extensively studied, only a few innate immune genes have been associated with GPP, namely IL36RN, AP1S3 and CARD14. Here, we sought to investigate the molecular pathogenesis of GPP using transcriptomic methods. We generated neutrophil RNAseq data (8 GPP cases vs 11 age and sex-matched controls), which we analysed using DESeq2 and Ingenuity Pathway Analysis (IPA). We first compared our neutrophil transcriptome with that generated by the Blueprint consortium for the same cell type, confirming the high purity of our samples. Next, we identified 200 genes that were up-regulated in patients vs controls (fold-change>1.5; FDR<0.05) and observed 7 enriched pathways (FDR<0.05), the strongest being IFN signaling (FDR<10-12). Moreover, a transcription factor (TF) enrichment analysis for the promoters of the upregulated genes highlighted an enrichment for IFN related activators. In keeping with these findings, a strong type-l-IFN signature was observed when comparing the expression of 5 Interferon stimulated genes (ISGs) in cases vs controls (P = 0.02). Validation by qPCR in a larger cohort confirmed the type-l-IFN signature in GPP (P = 7.5 x 10~-4) but not in localised forms of pustular psoriasis. Finally, even if the strongest genetic link with GPP is IL36RN, we showed that neutrophils do not respond to IL-36 stimulation nor express IL36R. These promising results implicate type-l-IFN signaling in the pathogenesis of GPP.