IL-17 Cytokines Induce IκBζ in Dermal Fibroblasts to Promote Pro-Inflammatory Gene Expression in Psoriasis

IκBζ (<i>NFKBIZ</i>) has been implicated as a key co-transcription factor in psoriasis pathogenesis. While its role in keratinocytes is well established, the involvement in dermal fibroblasts, another critical skin cell type, remains underexplored. This study characterizes cytokine-induced <i>NFKBIZ</i> regulation in human dermal fibroblasts in vitro and integrates spatial transcriptomics to determine <i>NFKBIZ</i> expression patterns in psoriatic skin biopsies. Primary dermal fibroblasts were stimulated with IL-17A, IL-17F, and TNF. Signaling pathways and gene regulation were examined using chemical inhibitors, siRNA knockdown, qPCR, and Western blotting. Additionally, spatial transcriptomics (CosMx™) assessed <i>NFKBIZ</i> expression in paired lesional and non-lesional psoriatic skin biopsies. Results showed significant upregulation of IκBζ expression in dermal fibroblasts following stimulation with both IL-17A and IL-17F. The NF-κB signaling pathway was identified as the primary regulator of <i>NFKBIZ</i> induction. <i>NFKBIZ</i> knockdown significantly reduced cytokine-induced expression of inflammatory mediators (CXCL8, CCL20, CCL2), confirming its regulatory role. Spatial transcriptomics further confirmed <i>NFKBIZ</i> expression in dermal fibroblasts in vivo, particularly in lesional psoriatic skin. This study establishes IκBζ as a critical modulator of inflammatory responses in dermal fibroblasts, expanding its recognized role beyond keratinocytes and immune cells, and highlights IκBζ inhibition as a potential therapeutic strategy.