Mechanoregulation of the epidermal immune response: the role of desmoglein 1

项目摘要 皮肤的表皮在生物体和环境之间提供了一道重要的屏障。颠覆 表皮屏障的缺失与牛皮癣和特应性皮炎等慢性炎症性疾病有关。 这些疾病患者的受累区域通常分布在发病率较高的地区。 机械应力的大小，例如牛皮癣的伸肌区和特应性皮炎的屈肌区。 这些疾病对机械应力敏感的潜在基础尚不清楚。桥粒是 细胞间连接对屏障的形成和提供机械强度都是至关重要的 表皮和丰富的组织经历了大量的机械应力。桥粒 钙粘蛋白Desmoglein 1(DSG1)仅在表皮等复层上皮细胞中表达，对 正常的表皮发育和功能。DSG1基因突变会导致严重的皮炎、多种过敏和 代谢性虚弱综合征是一种慢性炎症性疾病，与反复发生的皮肤感染有关， 表皮分化异常，角质形成细胞间黏附丧失。这些患者的屏障缺陷 可能可以解释皮肤中存在的一些炎症；然而，分离的角质形成细胞继续表达 细胞培养中促炎症细胞因子水平升高。DSG1在正常原代角质形成细胞中的表达下调 也会导致促炎细胞因子的表达增加。这些数据增加了DSG1 有助于炎症反应。其他证据表明，DSG1可能是一种压力传感器。DSG1是 被几种类型的环境压力下调，包括暴露在紫外线下。初步数据显示， DSG1在暴露于机械应力下的分化角质形成细胞中下调。机械应力也 角质形成细胞中促炎症细胞因子的表达增加，其中许多与增加的细胞因子重叠 DSG1基因敲除后角质形成细胞中的表达。这一提议将检验DSG1是一种机械 压力感应器，调节表皮炎症反应。目标1试图通过以下方式确定该机制 其中DSG1调控角质形成细胞中细胞因子的表达。这一目标也将检验美国在多大程度上 机械应激时DSG1表达下调，调节细胞因子表达增加。目标2将 确定机械应力下调角质形成细胞DSG1水平的分子机制。 初步数据表明，氧化应激也下调了DSG1的表达，以及下调的程度 机械损伤引起的氧化应激增加下调DSG1的作用将被测试。增加我们的 了解机械应力驱动炎症反应的机制将改善我们的 了解牛皮癣和特应性皮炎等疾病，并可能确定新的治疗目标 开发更有效的治疗方法。

Project Summary The epidermis of the skin provides an essential barrier between the organism and the environment. Disruption of the epidermal barrier is associated with chronic inflammatory diseases such as psoriasis and atopic dermatitis. Affected areas in patients with these diseases are frequently distributed in regions that experience higher amounts of mechanical stress, such as the extensor areas in psoriasis and flexor regions in atopic dermatitis. The underlying basis of sensitivity to mechanical stress in these diseases is unknown. Desmosomes are intercellular junctions that are critical for both formation of the barrier and for providing mechanical strength to the epidermis and are abundant in tissues that experience large amounts of mechanical stress. The desmosomal cadherin Desmoglein 1 (Dsg1) is only expressed in stratified epithelium such as the epidermis and is critical for proper epidermal development and function. Mutations in Dsg1 causes severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome, a chronic inflammatory disease associated with recurrent skin infections, abnormal epidermal differentiation and loss of adhesion between keratinocytes. Barrier defects in these patients may explain some of the inflammation present in the skin; however, isolated keratinocytes continue to express increased proinflammatory cytokine levels in cell culture. Knockdown of Dsg1 in normal primary keratinocytes also causes an increase in proinflammatory cytokine expression. These data raise the possibility that Dsg1 contributes to inflammatory responses. Other evidence indicates that Dsg1 may act as a stress sensor. Dsg1 is downregulated by several types of environmental stress, including exposure to UV. Preliminary data show that Dsg1 is downregulated in differentiated keratinocytes exposed to mechanical stress. Mechanical stress also increases expression of proinflammatory cytokines in keratinocytes, many of which overlap with those increased in keratinocytes after knockdown of Dsg1. This proposal will test the hypothesis that Dsg1 is a mechanical stress sensor and regulates epidermal inflammatory responses. Aim 1 seeks to identify the mechanism by which Dsg1 regulates cytokine expression in keratinocytes. This aim will also test the extent to which the downregulation of Dsg1 in response to mechanical stress regulates increased cytokine expression. Aim 2 will determine the molecular mechanism by which mechanical stress downregulates Dsg1 levels in keratinocytes. Preliminary data indicate that Dsg1 is also downregulated in response to oxidative stress, and the extent to which increased oxidative stress induced by mechanical insult downregulates Dsg1 will be tested. Increasing our knowledge of mechanisms by which mechanical stress drives inflammatory responses will improve our understanding of diseases such as psoriasis and atopic dermatitis, and potentially identify new targets for developing more effective therapies.