CYLD Limits Neutrophil-Driven Psoriatic Inflammation

Abstract 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, we 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. The results showed 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. Bioinformatics analyses confirmed CYLD was closely associated with pathways related to neutrophil migration and activation. These findings lead 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.