Laboratory of Cutaneous Biology, Service of Dermatology and Venereology, Beaumont Hospital CHUV, Lausanne, Switzerland.
PLoS One. 2013 Jul 3;8(7):e67869. doi: 10.1371/journal.pone.0067869. Print 2013.
Loss-of-function mutations in human profilaggrin gene have been identified as the cause of ichthyosis vulgaris (IV), and as a major predisposition factor for atopic dermatitis (AD). Similarly, flaky tail (a/a ma ft/ma ft/J) mice were described as a model for IV, and shown to be predisposed to eczema. The aim of this study was to correlate the flaky tail mouse phenotype with human IV and AD, in order to dissect early molecular events leading to atopic dermatitis in mice and men, suffering from filaggrin deficiency. Thus, 5-days old flaky tail pups were analyzed histologically, expression of cytokines was measured in skin and signaling pathways were investigated by protein analysis. Human biopsies of IV and AD patients were analyzed histologically and by real time PCR assays. Our data show acanthosis and hyperproliferation in flaky tail epidermis, associated with increased IL1β and thymic stromal lymphopoietin (TSLP) expression, and Th2-polarization. Consequently, NFκB and Stat pathways were activated, and IL6 mRNA levels were increased. Further, quantitative analysis of late epidermal differentiation markers revealed increased Small proline-rich protein 2A (Sprr2a) synthesis. Th2-polarization and Sprr2a increase may result from high TSLP expression, as shown after analysis of 5-days old K14-TSLP tg mouse skin biopsies. Our findings in the flaky tail mouse correlate with data obtained from patient biopsies of AD, but not IV. We propose that proinflammatory cytokines are responsible for acanthosis in flaky tail epidermis, and together with the Th2-derived cytokines lead to morphological changes. Accordingly, the a/a ma ft/ma ft/J mouse model can be used as an appropriate model to study early AD onset associated with profilaggrin deficiency.
人类前丝聚合蛋白基因的功能丧失突变已被确定为寻常型鱼鳞病（IV）的病因，也是特应性皮炎（AD）的主要易患因素。同样，鳞屑尾（a/a ma ft/ma ft/J）小鼠被描述为 IV 的模型，并显示易患湿疹。本研究旨在将鳞屑尾小鼠表型与人类 IV 和 AD 相关联，以剖析导致患有丝聚合蛋白缺陷的人类和小鼠特应性皮炎的早期分子事件。因此，分析了 5 天大的鳞屑尾幼鼠的组织学特征，测量了皮肤中的细胞因子表达，并通过蛋白质分析研究了信号通路。分析了 IV 和 AD 患者的活检组织的组织学和实时 PCR 检测结果。我们的数据显示，鳞屑尾表皮的棘层肥厚和过度增殖，与白细胞介素 1β和胸腺基质淋巴细胞生成素（TSLP）表达增加以及 Th2 极化有关。因此，NFκB 和 Stat 通路被激活，IL6 mRNA 水平增加。此外，对晚期表皮分化标志物的定量分析显示，Small proline-rich protein 2A（Sprr2a）的合成增加。Th2 极化和 Sprr2a 增加可能是由于 TSLP 表达增加所致，这是通过分析 5 天大的 K14-TSLP tg 小鼠皮肤活检组织得出的。我们在鳞屑尾小鼠中发现的结果与 AD 患者活检组织获得的数据相关，但与 IV 无关。我们提出，促炎细胞因子是导致鳞屑尾表皮棘层肥厚的原因，与 Th2 衍生的细胞因子一起导致形态学变化。因此，a/a ma ft/ma ft/J 小鼠模型可用于研究与前丝聚合蛋白缺陷相关的早期 AD 发病。
