IκBζ is a key player in the antipsoriatic effects of secukinumab

Abstract

Background: IkBz plays a key role in psoriasis by mediating IL-17A-driven effects, but the molecular mechanism by which IL-17A regulates IkBz expression is not clarified. Objective: We sought to explore the molecular transformation in patients with psoriasis during anti-IL-17A (secukinumab) treatment with a focus on IkBz. Methods: The study was an open-label, single-arm, single-center secukinumab treatment study that included 14 patients with plaque psoriasis. Skin biopsy specimens and blood samples were collected on days 0, 4, 14, 42, and 84 and processed for microarray gene expression analysis. Furthermore, in vitro experiments with human keratinocytes and synovial fibroblasts were conducted. Results: Secukinumab improved clinical scores and histologic psoriasis features. Moreover, secukinumab altered the skin transcriptome. The major transcriptional shift appeared between day 14 and day 42 after treatment initiation, although 80 genes were differentially expressed already at day 4. Expression of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor (IkB) z (NFKBIZ, the gene encoding IkBz) was reduced already after 4 days of treatment in the skin. NFKBIZ expression correlated to Psoriasis Area and Severity Index score, and NFKBIZ mRNA levels in the skin decreased during anti-IL-17A treatment. Moreover, specific NFKBIZ signature genes were significantly altered during anti-IL-17A treatment. Finally, we identified NF-kB activator 1 (Act1), p38 mitogen-activated protein kinase (MAPK), Jun NH2-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) as key signaling pathways in NFKBIZ/IkBz regulation. Conclusion: Our results define a crucial role for IkBz in the antipsoriatic effect of secukinumab. Because IkBz signature genes were regulated already after 4 days of treatment, this strongly indicates that IkBz plays a crucial role in the antipsoriatic effects mediated by anti-IL-17A treatment. (J Allergy Clin Immunol 2020;145:379-90.)

The HSP90 inhibitor RGRN‐305 exhibits strong immunomodulatory effects in human keratinocytes

“…Keratinocytes are increasingly thought to play a key role in initiating the development of psoriasis as well as in amplifying the psoriatic inflammation during maintenance of lesions 7,28,29 . Moreover, studies in human keratinocytes have shown that IκBζ (the protein encoded by NFKBIZ ) is a key transcriptional regulator of CCL20 , IL36G and IL23A gene expression, 10,30,31 three genes known to play a crucial role in the psoriasis pathogenesis 1,10,24 . Thus, it is possible that RGRN‐305 mediates its immunomodulatory effects in human keratinocytes by inhibiting the IL‐17A+TNFα‐induced IκBζ expression and subsequently the expression of CCL20 , IL36G and IL23A as well as other IκBζ‐regulated genes.…”

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

“…Psoriasis is well-known as an autoimmune disease of the joints and skin with inappropriate T cell activation. The transcriptional activator IκBζ induced by IL-17A-treated epithelial cells plays a key role in mediating the orchestrates downstream inflammatory responses in immune-related conditions, psoriasis (Bambouskova et al, 2018 ; Bertelsen et al, 2020 ). DI pretreatment interfere with the production of IκBζ in a way of electrophilic stress mediated by ATF3, a key mediator of the Nrf2-independent way and downregulate IκBζ protein correlated genes in primary keratinocytes stimulated by IL-17A (Bambouskova et al, 2018 ).…”

Key Signaling Pathways in Psoriasis: Recent Insights from Antipsoriatic Therapeutics

“… 57 IκBζ (encoded by NFKBIZ ) has been proposed to play a key role in mediating the effects of IL-17A and IL-17F. 59–61 …”