CYLD Limits Neutrophil-Driven Psoriatic Inflammation

Despite the well-recognized role of the deubiquitinase CYLD in the pathogenesis of tumors and certain inflammatory diseases, its specific function and regulatory mechanisms in psoriasis remain unclear; thus, we first analyzed CYLD expression differences between psoriatic patients and healthy controls using skin samples from the GEO database and validated its expression dynamics in an imiquimod (IMQ)-induced mouse model, then systematically evaluated the effects of CYLD deficiency on psoriasiform inflammation through histopathology, immunohistochemistry, RNA sequencing, and immunofluorescence analyses using Cyld knockout ( Cyld ^−/− ) mice, and employed bioinformatics approaches including CIBERSORT and Weighted Gene Co-expression Network Analysis (WGCNA) to further explore the associations between CYLD and neutrophil-related pathways and genes, with results showing that CYLD expression was significantly upregulated in lesional skin of psoriasis patients, Cyld ^−/− mice displayed more severe psoriasiform symptoms (enhanced epidermal thickening, increased neutrophil infiltration, significantly augmented formation of neutrophil extracellular traps [NETs]), CYLD deficiency led to excessive activation of the NF-κB signaling pathway and upregulated expression of various pro-inflammatory cytokines and chemokines, and bioinformatics analyses confirmed CYLD was closely associated with pathways related to neutrophil migration and activation, leading to the conclusion that CYLD plays a crucial negative regulatory role in psoriasis by inhibiting NF-κB-mediated neutrophil activation and NETs formation, so targeted activation of CYLD may represent a promising novel therapeutic strategy for psoriasis.