Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2 Leads to the Development of Psoriasis
Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2 Leads to the Development of Psoriasis
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DOI：
10.2353/ajpath.2009.080858
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发表时间：
2009-04-01
影响因子：
6
通讯作者：
Ward, Nicole L.
中科院分区：
文献类型：
--
作者：
Wolfram, Julie A.;Diaconu, Doina;Ward, Nicole L.
银屑病是通过角质形成细胞、血管、基因表达和免疫系统之间的多方面相互作用而启动和维持的。以前的一种银屑病模型显示，血管生成素受体Tie2在内皮细胞和角质形成细胞中的过度表达导致银屑病样表型的发展；然而，仅在每种细胞类型中过度表达的病因学意义尚不清楚。我们现在已经设计了两个新的小鼠模型，在这个模型中，Tie2的表达仅限于内皮细胞或角质形成细胞。这两个品系的小鼠的真皮血管都显著增加，但只有KC-Tie2过表达的小鼠出现了皮肤牛皮癣样表型。这些小鼠自发地出现人类银屑病的特征特征，包括广泛的棘皮病，真皮CD4(+)T细胞增加，浸润性表皮CD8(+)T细胞，真皮树突状细胞和巨噬细胞，以及与银屑病相关的细胞因子和趋化因子的表达增加，包括干扰素-伽玛、肿瘤坏死因子-α和白介素6、12、22、23和17。在过度增殖的皮肤中，宿主防御分子、放线菌素、β-防御素和S100A8/A9也上调。在抑制转基因后，所有的表型特征都完全逆转，没有任何疤痕，在使用抗牛皮癣系统疗法环孢菌素A治疗后，这些表型特征得到了显著改善。因此，仅将Tie2的过度表达限制在角质形成细胞上，可以产生符合人类牛皮癣动物模型所需的临床、组织学、免疫表型、生化和药理学标准的小鼠模型。(Am J Pathol 2009174：1443-1458；DOI：10.2353/ajpath.2009.080858)
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 la, 6, 12, 22, 23, and 17. Host-defense molecules, cathelicidin, beta-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. (Am J Pathol 2009, 174:1443-1458; DOI: 10.2353/ajpath.2009.080858)