Regulation of Skin Inflammation by Nociceptive Sensory Neurons

 描述（由申请人提供）：炎症性皮肤病，如银屑病、特应性皮炎和接触性超敏反应，通常伴有令人不快的疼痛和瘙痒感。目前尚不清楚这些不适感是否以及在何种程度上可能在引发和维持皮肤炎症中起积极作用。这一领域的工作必须考虑到，有不同的伤害性外周神经纤维的子集，传递不同的疼痛刺激，包括有害的热，冷，机械压力和瘙痒。 在这个项目的初步工作中，我们发现，一个子集的感觉神经元对特定的疼痛刺激是必不可少的发展银屑病样皮炎在小鼠皮肤。在该模型中，炎症通过细胞因子白细胞介素（IL）-23和IL-17的局部产生来启动和维持。使用选择性伤害感受器消融的药理学和遗传学模型，我们观察到特定的感觉神经元与皮肤驻留的树突状细胞（DC）非常接近，并且对于DC产生IL-23是至关重要的，这是促进皮肤T细胞随后分泌IL-17所必需的。在这里，我们建议测试的假设，即皮肤体感伤害感受器发挥了积极的作用，通过控制组织驻留免疫细胞的关键细胞因子的生产，在调节炎症皮肤反应。我们的实验方法将使我们能够定义不同的疼痛感觉如何有助于调节先天和适应性皮肤免疫系统的不同分支。如果成功，这些目标将增强我们对屏障组织中神经免疫相互作用的基础知识，并确定新的治疗靶点，以减轻和治疗炎症性皮肤病。 为了验证我们的假设，我们提出了两个目标，并得到了广泛的初步数据的支持：目标1：研究伤害性感觉神经元对皮肤炎症反应的影响。我们将提供一个全面的概述不同的疼痛模式和炎症模块之间的关系，驱动类型1，类型2或类型17的皮肤反应目的2。描述伤害感受器对树突状细胞的调控。我们将表型和可视化树突状细胞的行为在皮肤神经调制的反应。

 DESCRIPTION (provided by applicant): Inflammatory skin conditions, such as psoriasis, atopic dermatitis and contact hypersensitivity are often associated with unpleasant sensations of pain and itch. It is unclear whether and to what extent these sensations of discomfort may play an active role in initiating and maintaining cutaneous inflammation. Work in this area must take into account that there are different subsets of nociceptive peripheral nerve fibers that transmit distinct painful stimuli, including noxious heat, cold, mechanical pressure and itch. In preliminary work for this project, we have discovered that a subset of sensory neurons responsive to specific painful stimuli is essential for the development of psoriasiform dermatitis in murine skin. In this model inflammation is initiated and sustained by the local production of the cytokines interleukin (IL)-23 and IL-17. Using both pharmacological and genetic models of selective nociceptor ablation, we observed that specific sensory neurons are in close proximity to skin-resident dendritic cells (DCs) and are critical for the production of IL-23 by DCs, which i necessary to promote subsequent IL-17 secretion by cutaneous T cells. Here we propose to test the hypothesis that dermal somatosensation by nociceptors plays an active role in regulating inflammatory skin responses by controlling the production of key cytokines by tissue-resident immune cells. Our experimental approach will allow us to define how distinct pain sensations contribute to regulating different branches of the innate and adaptive cutaneous immune system. If successful, these aims will enhance both our fundamental knowledge of neuro-immune interactions at a barrier tissue and also identify novel therapeutic targets to alleviate and treat inflammatory skin disease. To test our hypothesis, we propose two Aims that are supported by extensive preliminary data: Aim 1: To investigate the impact of nociceptive sensory neurons on cutaneous inflammatory responses. We will provide a comprehensive overview of the relationship between distinct pain modalities and inflammatory modules that drive Type 1, Type 2 or Type 17 responses in the skin Aim 2. To characterize the regulation of dendritic cells by nociceptors. We will phenotype and visualize dendritic cell behavior in response to neural modulation in the skin.