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 2

Keratinocyte-specific deletion of IκBζ protects against IMQ-induced psoriasis.

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Keratinocyte-specific deletion of IκBζ protects against IMQ-induced psor...
All analyses were performed after 7 days of IMQ treatment. (A) Measurement of the ear thickness from global and K14-KO mice during 7 days of daily IMQ treatment. Top: TAM-treated control (Ctrl) and global Nfkbiz-KO mice. n = 6. Bottom: Control and K14-Nfkbiz–KO mice. n = 20. (B) H&E staining from ears of untreated and IMQ-treated mice. Scale bars: 100 μm. (C) IHC detection of infiltrating neutrophils (marker myeloperoxidase [MPO]) and macrophages (marker F4/80) in untreated and IMQ-treated K14-KO mice. Scale bars: 50 μm. (D) Quantification of infiltrating neutrophils (Ly6G+) and macrophages (F4/80+) by flow cytometry analysis. Depicted is the relative number of infiltrating immune cells from whole ears of untreated and IMQ-treated mice. n = 3–4 ± SEM. (E) Gene expression analysis of untreated and IMQ-treated control and K14-KO mice. Relative mRNA expression of psoriasis-related genes was analyzed from 4–14 ear skin samples per group ± SEM and normalized to the reference gene Actin. P values were calculated using 2-tailed Student’s t test (*P < 0.05, **P < 0.01, and ***P < 0.001).