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

Area of Science:

• Dermatology
• Immunology
• Molecular Biology

Background:

• Nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor zeta (NFKBIZ) is a key co-transcription factor in psoriasis pathogenesis.
• Its role in keratinocytes is established, but its function in dermal fibroblasts is underexplored.

Purpose of the Study:

• To characterize cytokine-induced NFKBIZ regulation in human dermal fibroblasts in vitro.
• To determine NFKBIZ expression patterns in psoriatic skin using spatial transcriptomics.

Main Methods:

• Human dermal fibroblasts were stimulated with IL-17A, IL-17F, and TNF.
• NFKBIZ regulation was studied using chemical inhibitors, siRNA, qPCR, and Western blotting.
• Spatial transcriptomics (CosMx™) analyzed NFKBIZ expression in psoriatic skin biopsies.

Main Results:

• IL-17A and IL-17F significantly upregulated NFKBIZ expression in dermal fibroblasts.
• The NF-κB pathway mediated NFKBIZ induction.
• NFKBIZ knockdown reduced inflammatory mediator expression (CXCL8, CCL20, CCL2).
• Spatial transcriptomics confirmed NFKBIZ expression in dermal fibroblasts in lesional psoriatic skin.

Conclusions:

• NFKBIZ is a critical regulator of inflammatory responses in dermal fibroblasts.
• This expands the known role of NFKBIZ beyond keratinocytes and immune cells.
• NFKBIZ inhibition presents a potential therapeutic strategy for psoriasis.