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Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins

A Corrigendum to this article was published on 30 March 2006

Abstract

Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads (within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 (TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.

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Figure 1: Reduced JunB expression in human psoriatic skin.
Figure 2: Inducible deletion of JunB and c- Jun in the epidermis of adult mice.
Figure 3: Mice lacking JunB and c- Jun in the epidermis exhibit the hallmarks of psoriasis.
Figure 4: Mice lacking JunB and c- Jun in the epidermis exhibit deregulated cytokine expression as observed in psoriasis.
Figure 5: Inducible deletion of JunB and c-Jun in Rag2 - and TNFR1 -deficient mice.

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Acknowledgements

We are grateful to M. Sibilia, G. Stingl, D. Maurer, J. Smolen, G. Schett and A. Rot for critical comments and suggestions to the manuscript, M. Cotton for providing adeno-Cre viruses, H. Tkadletz for help in preparing the illustrations and J. Hess for support with S100 protein expression analyses. The IMP is funded by Boehringer Ingelheim and this work was supported by grants from the Austrian Research Foundation, the Deutsche Forschungsgemeinschaft and by the Research Training Network (RTN) Program of the European Community.

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Correspondence to Erwin F. Wagner.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

No psoriasis following single epidermal deletion of either JunB or c-Jun. (JPG 246 kb)

Supplementary Figure S2

Cytokine expression after 4 days following three Tam injections. (JPG 364 kb)

Supplementary Figure S3

Cytokine expression after 18 days following Tam injections. (JPG 111 kb)

Supplementary Figure S4

Induction of JunB/c-Jun deletion in the presence of ciprofloxacin. (JPG 1140 kb)

Supplementary Figures Legends

Text to accompany the above Supplementary Figures. (DOC 21 kb)

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Zenz, R., Eferl, R., Kenner, L. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369–375 (2005). https://doi.org/10.1038/nature03963

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