The Effect of IL-4 Receptor Singaling on Inflammation and Skin Barrier Function i

特应性皮炎的发生是由于对常见元素的不适当免疫反应。 环境。辅助性T细胞II型(Th2)是病理性炎症的关键因素 在这些患者中观察到的反应。例如，特应性皮炎的特征是增加了 皮肤中的Th2细胞因子IL-4和IL-13。当角质形成细胞与IL-4或IL-13共同培养时， 通过产生各种促炎介质进行反应，它们会失去微丝蛋白和 氯蛋白和总蛋白，这是维持皮肤屏障功能的重要蛋白质。然而，有一些 目前还没有研究表明IL-4和IL-13直接作用于角质形成细胞的体内相关性。 与特应性皮炎相关的病理学。IL-4和IL-13通过连接共同受体IL-4和IL-13来传递信号 4ra.我们的假设是，IL-4Ra信号在角质形成细胞中特异性地参与炎症和 特应性皮炎小鼠模型中皮肤屏障功能的丧失。主要目标是确定 皮肤病理发展中角质形成细胞特异性表达IL-4ra的体内需求 与实验性特应性皮炎有关。我们将通过完成两个具体的目标来实现这一目标 目标。特定目标1：产生一种IL-4ra独有缺陷的突变小鼠品系 角质形成细胞。我们将用我们的IL-4Ra FLOX/FLOX小鼠培育商业上可用的K14-CRE小鼠。K14- Cre小鼠仅在角质形成细胞中表达Cre重组酶(Cre)。IL-4Ra FLOX/FLOX小鼠具有凝固性 IL-4ra基因外显子7-9两侧的loxP序列。当这两个品系的小鼠被培育出来时， 双突变小鼠仅在角质形成细胞中表达Cre，导致角质形成细胞特异性缺失 IL-4ra基因。否则，这些小鼠在所有其他类型的细胞中都有正常的IL-4和IL-13信号。 特定目的2：确定角质形成细胞特异性表达IL-4Rct的体内需求 与实验性特应性皮炎相关的皮肤病理学进展。我们预计老鼠会有 角质形成细胞特异性IL-4ra缺失将免受炎症和皮肤屏障功能丧失的影响 这在特应性皮炎的小鼠模型中得到了很好的启发。

Atopic dermatitis occurs as a result of inappropriate immune responses to common elements in the environment. The T-helper type II (Th2) lymphocyte is a critical contributor to the pathologic inflammatory responses observed in these patients. For example, atopic dermatitis is characterized by increased levels of the Th2 cytokines, IL-4 and IL-13, in the skin. When keratinocytes are cultured with either IL-4 or IL-13 they respond by producing a variety of pro-inflammatory mediators and they lose expression of filaggrin as well as loricrin and involucrin, which are important proteins that maintain skin barrier function. However, there have been no studies performed to test the in vivo relevance of IL-4 and IL-13 acting directly on keratinocytes in the pathologies associated with atopic dermatitis. IL-4 and IL-13 signal by ligation of a common receptor, IL- 4Ra. Our hypothesis is that IL-4Ra signaling specifically in keratinocytes contributes to inflammation and failure of skin barrier function in a murine model of atopic dermatitis. The main objective is to determine the in vivo requirement for keratinocyte-specific expression of IL-4Ra in the development of skin pathologies associated with experimental atopic dermatitis. We will accomplish this objective by completing two specific aims. Specific Aim 1: To generate a mutant mouse strain that is deficient in IL-4Ra exclusively in keratinocytes. We will breed commercially available K14-Cre mice with our IL-4Ra flox/flox mice. The K14- Cre mice have expression of Cre-recombinase (Cre) only in keratinocytes. IL-4Ra flox/flox mice have Crebinding loxP sequences that flank exons 7 -9 of the IL-4Ra gene. When the two strains of mice are bred, the double mutant mice have expression of Cre only in keratinocytes causing keratinocyte-specific deletion of the IL-4Ra gene. Otherwise, these mice have normal IL-4 and IL-13 signaling in every other cell type. Specific Aim 2: To determine the in vivo requirement for keratinocyte-specific expression of IL-4Rct in the development of skin pathology associated with experimental atopic dermatitis. We anticipate that mice with keratinocyte-specific IL-4Ra deletion will be protected from inflammation and failure of skin barrier function as elicited in a well-characterized mouse model of atopic dermatitis.