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

## TL;DR

This study shows that IκBζ helps promote inflammation in skin fibroblasts in psoriasis, suggesting it could be a new target for treatment.

## Contribution

The study identifies IκBζ regulation in dermal fibroblasts as a novel mechanism in psoriasis inflammation.

## Key findings

- IL-17A and IL-17F significantly upregulate IκBζ in dermal fibroblasts.
- NFKBIZ knockdown reduces inflammatory mediator expression in fibroblasts.
- Spatial transcriptomics confirms IκBζ expression in lesional psoriatic skin.

## Abstract

IκBζ (NFKBIZ) 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 NFKBIZ regulation in human dermal fibroblasts in vitro and integrates spatial transcriptomics to determine NFKBIZ 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 NFKBIZ 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 NFKBIZ induction. NFKBIZ knockdown significantly reduced cytokine-induced expression of inflammatory mediators (CXCL8, CCL20, CCL2), confirming its regulatory role. Spatial transcriptomics further confirmed NFKBIZ 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.