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 1

NFKBIZ expression in mouse and human skin.

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NFKBIZ expression in mouse and human skin. (A) Induction of IκBζ in who...
(A) Induction of IκBζ in whole-skin lysates from untreated and IMQ-treated, TAM-induced global (KO, upper) or keratinocyte-specific (K14-KO, lower) IκBζ-deficient mice at day 7. Actin served as a loading control. (B) Predominant localization of Nfkbiz in the epidermis of IMQ-treated control mice, which is absent in IMQ-treated K14-KO mice. Scale bars: 40 μm. (C) Keratinocyte-specific NFKBIZ expression was also detected in normal human skin (upper). As shown by the increased number of red dots, NFKBIZ expression was elevated in human psoriatic skin lesions (lower). Following deparaffinization tissue sections were hybridized with mouse or human NFKBIZ-specific RNAScope target probe sets consisting of multiple tandem short oligonucleotides. NFKBIZ mRNAs were visualized as dots, with each dot representing a single RNA transcript. Right images show sections of the pictures on the left at a higher magnification. Scale bars: 100 μm.