Analysis of the potential pyroptosis mechanism in psoriasis and experimental validation of NLRP3 in vitro and in vivo

Abstract

Pyroptosis provides new perspectives on the mechanisms underlying psoriasis and the development of new treatment strategies. Here, we aimed to identify pyroptosis-related genes (PRGs) involved in the pathogenesis and progression of psoriasis. Based on the inclusion/exclusion criteria, three gene datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differential gene expression, weighted gene co-expression network analysis (WGCNA), and functional enrichment analyses were performed to identify candidate PRGs for psoriasis. Least absolute shrinkage and selection operator (LASSO) regression was used to identify hub genes, and receiver operating characteristic (ROC) curves were used to determine the clinical value of the hub genes. Imiquimod-inducedpsoriasis-like mice and lipopolysaccharide (LPS)-induced RAW 264.7 cells were employed to verify the pro-inflammatory factors that may drive changes in pyroptosis. In total, 159 skin samples were analysed, and a total of 21 common targets were obtained by crossing PRGs with all the differentially expressed genes (DEGs) in different disease states. 11 genes were identified via LASSO screening. Similarly, the last six PRGs biomarkers and the green module genes were screened. All hub genes with an area under the ROC curve > 0.5 were intersected, and NLRP3 was identified. NLRP3 expression was elevated in imiquimod-induced psoriatic lesions in mice and LPS-stimulated RAW 264.7 cells. The mice exhibited reduced psoriasis area and severity index scores, hyperproliferation, and inflammation after treatment with MCC950 (a specific inhibitor of NLRP3). MCC950 decreased IL-1β, IL-6, and TNF-α mRNA expression, and NLRP3 and p-p65 protein levels in LPS-stimulated RAW 264.7 cells. Our study indicates that NLRP3 may be a promising therapeutic target for the treatment of psoriasis.

Keywords: Differentially expressed genes, DEGs; Inflammatory disease; NLRP3 Inflammasome; Psoriasis; Pyroptosis; Weighted gene co-expression network analysis.