Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Department of Dermatology and Plastic Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Sci Rep. 2016 Oct 4;6:34690. doi: 10.1038/srep34690.
Psoriasis is a chronic inflammatory skin disease marked by aberrant tissue repair. Mutant mice modeling psoriasis skin characteristics have provided useful information relevant to molecular mechanisms and could serve to evaluate therapeutic strategies. Here, we found that epidermal ANGPTL6 expression was markedly induced during tissue repair in mice. Analysis of mice overexpressing ANGPTL6 in keratinocytes (K14-Angptl6 Tg mice) revealed that epidermal ANGPTL6 activity promotes aberrant epidermal barrier function due to hyperproliferation of prematurely differentiated keratinocytes. Moreover, skin tissues of K14-Angptl6 Tg mice showed aberrantly activated skin tissue inflammation seen in psoriasis. Levels of the proteins S100A9, recently proposed as therapeutic targets for psoriasis, also increased in skin tissue of K14-Angptl6 Tg mice, but psoriasis-like inflammatory phenotypes in those mice were not rescued by S100A9 deletion. This finding suggests that decreasing S100A9 levels may not ameliorate all cases of psoriasis and that diverse mechanisms underlie the condition. Finally, we observed enhanced levels of epidermal ANGPTL6 in tissue specimens from some psoriasis patients. We conclude that the K14-Angptl6 Tg mouse is useful to investigate psoriasis pathogenesis and for preclinical testing of new therapeutics. Our study also suggests that ANGPTL6 activation in keratinocytes enhances psoriasis susceptibility.
银屑病是一种慢性炎症性皮肤病，其特征是组织修复异常。模拟银屑病皮肤特征的突变小鼠为分子机制提供了有用的信息，并可用于评估治疗策略。在这里，我们发现，在组织修复过程中，表皮 ANGPTL6 的表达在小鼠中明显上调。对角质形成细胞过表达 ANGPTL6 的小鼠（K14-Angptl6 Tg 小鼠）的分析表明，表皮 ANGPTL6 活性通过过早分化的角质形成细胞的过度增殖促进异常的表皮屏障功能。此外，K14-Angptl6 Tg 小鼠的皮肤组织表现出银屑病中所见的异常激活的皮肤组织炎症。最近被提议作为银屑病治疗靶点的蛋白质 S100A9 的水平也在 K14-Angptl6 Tg 小鼠的皮肤组织中增加，但 S100A9 缺失并未挽救这些小鼠的银屑病样炎症表型。这一发现表明，降低 S100A9 水平可能无法改善所有银屑病病例，并且该疾病的发病机制多种多样。最后，我们观察到一些银屑病患者的组织标本中表皮 ANGPTL6 水平升高。我们得出结论，K14-Angptl6 Tg 小鼠可用于研究银屑病发病机制和新型治疗药物的临床前测试。我们的研究还表明，角质形成细胞中 ANGPTL6 的激活增强了银屑病的易感性。
