FC17 Inducible deletion of Mettl3 in murine keratinocytes induces spontaneous inflammation: a novel model for palmoplantar pustulosis and palmoplantar pustular psoriasis

Abstract Palmoplantar pustulosis (PPP) and palmoplantar pustular psoriasis (PPPP) are chronic inflammatory skin conditions characterized by the eruption of sterile pustules on the palms and/or soles. Although several animal models have been established for plaque psoriasis, no models currently exist for PPP or PPPP. In this study, we demonstrate that the inducible deletion of METTL3, an m6A RNA methyltransferase, in murine keratinocytes results in spontaneous, sterile skin inflammation localized exclusively to the palms, soles, and tail. Histopathological examination revealed intraepidermal accumulation of neutrophils and the formation of subcorneal pustules. Transcriptomic sequencing showed that the gene expression profile of the tail lesions closely resembles that of psoriatic lesions in human patients. In the palm lesions, differential gene expression analysis identified pathways associated with leukocyte chemotaxis, migration, and inflammatory responses. KEGG enrichment analysis highlighted several relevant signalling pathways, including the IL-17 signalling pathway, cytokine-cytokine receptor interaction, TNF signalling pathway, and NF-kappa B signalling pathway, etc. Importantly, inflammation-related genes such as Il1b, Il6, and Il19, along with neutrophil chemotaxis-related genes (Cxcl1, Cxcl2, Cxcl3, Cxcl5, and Cxcl15) and antimicrobial peptides (S100a7/8/9 and Defb4), exhibited significantly elevated expression levels in our model, correlating with findings in patient PPP lesions. RT-qPCR further validated our transcriptomic results, while immunofluorescence staining revealed a substantial accumulation of neutrophils at the lesion sites. This study provides a valuable model and foundational basis for future research into PPP and PPPP, laying the basis for new investigations in this field.