Regulation of Skin Inflammation by Nociceptive Sensory Neurons

 描述(申请人提供)：炎症性皮肤状况，如牛皮癣、特应性皮炎和接触性过敏，通常与疼痛和瘙痒的不适感觉有关。目前尚不清楚这些不适感是否以及在多大程度上可能在启动和维持皮肤炎症方面发挥积极作用。这一领域的工作必须考虑到，有不同的伤害性周围神经纤维亚群传递不同的疼痛刺激，包括伤害性的热、冷、机械压力和瘙痒。在这个项目的前期工作中，我们发现对特定疼痛刺激有反应的感觉神经元的子集在小鼠皮肤银屑病样皮炎的发生中是必不可少的。在这个模型中，炎症是由局部产生的细胞因子白介素23和白介素17启动和维持的。利用选择性伤害性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树突状细胞(DC)密切相关，并对DC产生IL-23至关重要，而DC产生IL-23是促进皮肤T细胞随后分泌IL-17所必需的。在这里，我们建议检验这一假设，即真皮伤害性感受器的躯体感觉通过控制组织驻留免疫细胞产生关键细胞因子，在调节炎症皮肤反应中发挥积极作用。我们的实验方法将使我们能够定义不同的痛感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，并确定减轻和治疗炎症性皮肤病的新治疗靶点。为了验证我们的假设，我们提出了两个目标，并得到了大量初步数据的支持：目标1：研究伤害性感觉神经元对皮肤炎症反应的影响。我们将全面概述不同的疼痛模式与驱动皮肤中1型、2型或17型反应的炎症模块之间的关系。2.表征伤害性感受器对树突状细胞的调节。我们将对树突状细胞的表型和行为进行可视化，以响应皮肤中的神经调节。

 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.