Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation
Sebastian Lorscheid, Anne Müller, Jessica Löffler, Claudia Resch, Philip Bucher, Florian C. Kurschus, Ari Waisman, Knut Schäkel, Stephan Hailfinger, Klaus Schulze-Osthoff, Daniela Kramer
Sebastian Lorscheid, Anne Müller, Jessica Löffler, Claudia Resch, Philip Bucher, Florian C. Kurschus, Ari Waisman, Knut Schäkel, Stephan Hailfinger, Klaus Schulze-Osthoff, Daniela Kramer
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Research Article Dermatology

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

Abstract

The transcriptional activator IκBζ is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that IκBζ expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of IκBζ in keratinocytes was sufficient to suppress the induction of imiquimod- or IL-36–mediated psoriasis. Moreover, IκBζ ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific IL-17A–transgenic mice. Mechanistically, this psoriasis protection was mediated by IκBζ deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Cxcl5, Cxcl2, Csf2, and Csf3, in response to IL-17A or IL-36. These IκBζ-dependent genes trigger the generation and recruitment of neutrophils and monocytes that are needed for skin inflammation. Consequently, our data uncover a surprisingly pivotal role of keratinocytes and keratinocyte-derived IκBζ as key mediators of psoriasis and psoriasis-related systemic inflammation.

Authors

Sebastian Lorscheid, Anne Müller, Jessica Löffler, Claudia Resch, Philip Bucher, Florian C. Kurschus, Ari Waisman, Knut Schäkel, Stephan Hailfinger, Klaus Schulze-Osthoff, Daniela Kramer

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Figure 4

Deletion of IκBζ in keratinocytes protects against IL-36–induced dermatitis.

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Deletion of IκBζ in keratinocytes protects against IL-36–induced dermati...
(A) Ear thickness of control Ctrl and K14-Cre Nfkbiz-KO mice that were treated with intradermal injections of PBS as control or 1 μg recombinant murine IL-36α for 5 consecutive days. n = 6, ± SEM. (B) H&E staining of ears from control and K14-KO mice at day 6. Scale bars: 100 μm. (C) IHC staining of macrophages (F4/80 staining) and neutrophils (MPO staining) in control and IL-36α–treated mice at day 6. Scale bars: 100 μm. (D) IκBζ mRNA and protein levels in IL-36α–treated ear skin samples. (E) Psoriasis-related gene expression in the ears of IL-36α–treated control and K14-KO mice with mean ± SEM from 2 to 3 PBS-treated and 6 IL-36α–treated animals per group. (F) Left: Gene expression in IL-36α–treated murine keratinocytes (mKC). Keratinocytes from 3 Ctrl and 3 K14-KO mice were isolated from the tails and grown to confluence. Upon treatment with 100 ng/mL IL-36α for 1.5 hours, cells were harvested and analyzed for gene expression. Relative mRNA levels were normalized to Actin. Right: Immunostaining of IκBζ in IL-36α–treated mKC. Control and KO cells were treated for 24 hours with 100 ng/mL IL-36α. (G) Detection of IκBζ binding to the promoters of psoriasis-related genes in keratinocytes. Left: ChIP of IκBζ or IgG as control was performed in untreated and IL-36α–treated mKC (treatment: 1.5 hours 100 ng/mL IL-36α). Shown is the fold enrichment of anti-IκBζ binding over IgG. The promoter region of myoglobulin (Mb) served as an internal negative control. n = 2 per group. Right: Detection of IκBζ levels in the chromatin fraction as input control. P values were calculated using 2-tailed Student’s t test (*P < 0.05, **P < 0.01, ***P < 0.001).