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

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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Correspondence to Shigetoshi Sano or John DiGiovanni.

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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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