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Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model

Nature Medicine volume 11, pages 43–49 (2005)Cite this article

Abstract

Here we report that epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively active Stat3 (K5.Stat3C mice) develop a skin phenotype either spontaneously, or in response to wounding, that closely resembles psoriasis. Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis.

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Figure 1: Epidermal keratinocytes of psoriatic lesions show activated Stat3.
Figure 2: Psoriatic lesions in K5.Stat3C mice.
Figure 3: Alterations associated with the psoriatic phenotype.
Figure 4: Involvement of T cells in generation of psoriatic phenotype.
Figure 5: Pretreatment with Stat3 decoy DNA prevents development of psoriatic lesions in K5.Stat3C mice.

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Acknowledgements

We thank V. Edwards and L. Beltran for editorial assistance. This work was supported by US National Institutes of Health grants CA76520 (J.D.), AR40065 (B.J.N), U01 ES11047, University of Texas M.D. Anderson Cancer Center Support Grant CA16672 and National Institute of Environmental Health Sciences Center Grant ES07784.

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Author notes

  1. Shigetoshi Sano and Keith Syson Chan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Carcinogenesis, Science Park - Research Division, University of Texas, M. D. Anderson Cancer Center, 1808 Park Road 1C, PO Box 389, Smithville, 78957, Texas, USA

    Shigetoshi Sano, Keith Syson Chan, Steve Carbajal, Mary Peavey, Kaoru Kiguchi & John DiGiovanni

  2. Department of Biochemistry and Molecular Biology, Louisiana State University, Health Sciences Center, School of Medicine in Shreveport and Feist-Weiller Cancer Center, 1501 Kings Highway, Shreveport, 71130, Louisiana, USA

    John Clifford

  3. Department of Dermatology, Osaka University Graduate School, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Satoshi Itami

  4. Department of Pathology and Department of Microbiology and Immunology, Loyola University of Chicago, Cardinal Bernardin Cancer Center, 2160 South First Avenue, Room 301, Maywood, 60153-5385, Illinois, USA

    Brian J Nickoloff

  5. Department of Dermatology, Osaka University Graduate School, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Shigetoshi Sano

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Supplementary information

Supplementary Fig. 1

Constitutive action of Stat3 in the uninvolved, adjacent epidermis of psoriatic patients. (PDF 725 kb)

Supplementary Fig. 2

Gross skin phenotypes of K5.Stat3C transgenic mice. (PDF 6209 kb)

Supplementary Fig. 3

Persistent psoriatic lesions in K5.Stat3C mice. (PDF 7046 kb)

Supplementary Fig. 4

TPA treatment (twice a week for one month) induced psoriatic skin lesions in K5.Stat3C mice (left panel) with histology (right bottom) identical to human psoriasis. (PDF 5095 kb)

Supplementary Fig. 5

Rapid upregulation of epidermal ICAM-1 by tape-stripping is Stat3-dependent. (PDF 802 kb)

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Sano, S., Chan, K., Carbajal, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 11, 43–49 (2005). https://doi.org/10.1038/nm1162

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