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(American Journal of Pathology. 2009;174:1443-1458.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080858

Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2 Leads to the Development of Psoriasis

Julie A. Wolfram*{dagger}, Doina Diaconu*, Denise A. Hatala*, Jessica Rastegar*, Dorothy A. Knutsen*, Abigail Lowther*, David Askew*{ddagger}, Anita C. Gilliam*, Thomas S. McCormick*§ and Nicole L. Ward*§

From the Departments of Dermatology,* Pathology,{dagger} Pediatrics,{ddagger} and Neuroscience, Case Western Reserve University, Cleveland; and The Murdough Family Center for Psoriasis,§ University Hospitals, Case Medical Center, Cleveland, Ohio

Psoriasis is initiated and maintained through a multifaceted interplay between keratinocytes, blood vessels, gene expression, and the immune system. One previous psoriasis model demonstrated that overexpression of the angiopoietin receptor Tie2 in endothelial cells and keratinocytes led to the development of a psoriasiform phenotype; however, the etiological significance of overexpression in each cell type alone was unclear. We have now engineered two new mouse models whereby Tie2 expression is confined to either endothelial cells or keratinocytes. Both lines of mice have significant increases in dermal vasculature but only the KC-Tie2-overexpressing mice developed a cutaneous psoriasiform phenotype. These mice spontaneously developed characteristic hallmarks of human psoriasis, including extensive acanthosis, increases in dermal CD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cells and macrophages, and increased expression of cytokines and chemokines associated with psoriasis, including interferon-{gamma}, tumor necrosis factor-{alpha}, and interleukins 1{alpha}, 6, 12, 22, 23, and 17. Host-defense molecules, cathelicidin, β-defensin, and S100A8/A9, were also up-regulated in the hyperproliferative skin. All of the phenotypic traits were completely reversed without any scarring following repression of the transgene and were significantly improved following treatment with the anti-psoriasis systemic therapeutic, cyclosporin A. Therefore, confining Tie2 overexpression solely to keratinocytes results in a mouse model that meets the clinical, histological, immunophenotypic, biochemical, and pharmacological criteria required for an animal model of human psoriasis.


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