Role of neurokinin 1 receptor signaling in keratinocytes in allergic contact dermatitis

摘要 过敏性接触性皮炎(ACD)是一种由皮肤暴露引起的高度常见的慢性炎症性皮肤病。 到半抗原，触发局部神经炎性反应，促进病毒型活化 1维持疾病慢性化的偏向效应T细胞。有一种未得到满足的具体需求 治疗ACD的免疫疗法，这些疗法的发展需要彻底了解 疾病的细胞和分子机制。 在半抗原穿透皮肤的过程中，通过促炎症反应传递神经激肽-1受体(NK1R)的信号 神经肽P物质和血激素-1促进皮肤炎症。这张促炎皮肤 环境是树突状细胞(DC)的T细胞刺激和1型偏向功能所必需的。 由于小鼠缺乏NK1R会损害ACD的发展，因此有观点认为，阻断NK1R 受体可能有益于治疗这种疾病。了解NK1R信号在免疫中的作用 对半抗原的反应对于试图抑制受体功能的治疗具有根本意义 来治疗ACD。尽管如此，半抗原的细胞和分子机制及其致病后果- 介导的NK1R在皮肤中的激活仍有待阐明。 角质形成细胞构成了接触性致敏剂影响的第一道防线，它们本身就具有 在皮肤启动的免疫反应的先天和适应性成分中的相关作用。角质形成细胞是主要的 构成表达NK1R的细胞亚群。使用NK1Rfl/fl小鼠，我们发表了特定的缺失 角质形成细胞中的NK1R损害IL-1β的合成和分泌，IL-1是激活角质形成细胞所必需的细胞因子 抑制ACD的先天免疫反应和获得性免疫反应。因此，我们 假设：角质形成细胞是半抗原介导的NK1R信号的早期细胞靶点，并且它们 是生成支持先天和效应器的促炎皮肤环境所必需的 ACD的免疫反应“。我们将在以下具体目标中解决这一假设。具体目标1将 分析NK1R信号转导途径对角质形成细胞促炎作用的机制 半身人。《特殊目的2》将分析角质形成细胞的细胞间通讯机制 在半抗原启动的皮肤过程中与皮肤常驻DC相互作用以促进其T细胞刺激功能 发炎。特异性目标3将分析NK1R信号在角质形成细胞中所起的作用 ACD效应性和记忆性T细胞的产生。我们的研究包括体外和体内小鼠模型。 和体外人类皮肤模型来测试我们实验的翻译相关性。如果成功，则数据 通过此应用程序生成的信息将为高效的开发提供高度相关的缺失信息 预防和治疗ACD的特殊疗法。

ABSTRACT Allergic contact dermatitis (ACD) is a highly common chronic inflammatory skin disease initiated by skin exposure to a hapten, which triggers local neuroinflammatory responses and promotes the activation of pathogenic Type 1 biased effector T cells that sustain the chronicity of the disease. There is an unmet need for specific immunotherapies to treat ACD, and development of these treatments requires a thorough understanding of the cellular and molecular mechanisms of the disease. During hapten penetration of the skin, signaling the neurokinin-1 receptor (NK1R) by the proinflammatory neuropeptides substance P and hemokinin-1 promotes cutaneous inflammation. This proinflammatory skin environment is required for the T cell-stimulatory and Type 1 biasing function of resident dendritic cells (DCs). Because lacking NK1R in mice impairs the development of ACD it has been proposed that blockade of the receptor could be beneficial to treat the disease. Understanding the impact of NK1R-signaling in the immune response to haptens is of fundamental relevance for therapies attempting to inhibit the function of the receptor to treat ACD. Nonetheless, the cellular and molecular mechanisms and the pathogenic consequences of hapten- mediated NK1R activation in the skin remain to be elucidated. Keratinocytes constitute the first line of defense affected by contact sensitizers and they have per se a relevant role in innate and adaptive components of skin-initiated immune responses. Keratinocytes are the main cell subset that expresses constitutively the NK1R. Using NK1Rfl/fl mice, we published that specific deletion of the NK1R in keratinocytes impairs the synthesis and secretion of IL-1β, a cytokine necessary for the activation of T-cell stimulatory DCs, and inhibits the innate and adaptive immune responses of ACD. Therefore, we hypothesize that: “Keratinocytes are early cell targets of hapten-mediated NK1R-signaling, and that they are required to generate the proinflammatory skin environment that supports the innate and effector immune responses of ACD”. We will address this hypothesis in the following specific aims. Specific aim 1 will analyze the mechanisms of the proinflammatory effects caused by NK1R-signaling in keratinocytes exposed to haptens. Specific aim 2 will analyze the mechanisms of intercellular communication by which keratinocytes interact with skin resident DCs to promote their T cell stimulatory functions during hapten initiated skin inflammation. Specific aim 3 will analyze the role of the NK1R-signaling exclusively in keratinocytes in the generation of the effector and memory T cells of ACD. Our studies include in vitro and in-vivo mouse models and ex-vivo human skin models to test the translational relevance of our experiments. If successful, the data generated through this application will provide highly relevant missing information for the development of efficient specific therapies for the prevention and treatment of ACD.