Regulation of Skin Inflammation by Nociceptive Sensory Neurons

伤害性感觉神经元对皮肤炎症的调节

• 批准号: 9268505
• 负责人: ULRICH H VON ANDRIAN
• 金额: $ 37.29万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268505
• 关键词: Ablation; Affect; Afferent Neurons; Area; Atopic Dermatitis; Bee Venoms; Bypass; Cell Communication; Cells; Communication; Complex; Contact hypersensitivity; Cutaneous; Data; Dendritic Cells; Dermal; Development; Esthesia; Genetic Models; Image; Imiquimod; Immune; Immune system; In Situ; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Instruction; Interleukin-12; Interleukin-17; Ion Channel; Knowledge; Light; Mechanics; Mediating; Modality; Modeling; Mouse Strains; Mus; Myeloid Cells; Natural Killer Cells; Nerve Fibers; Neuroimmune; Neurons; Nociception; Nociceptors; Pain; Patients; Peripheral Nerves; Pharmacology; Phenotype; Play; Positioning Attribute; Process; Production; Pruritus; Psoriasiform Dermatitis; Psoriasis; Reaction; Recombinant Interleukins; Recruitment Activity; Regulation; Role; Sensory; Skin; Source; Specificity; Stimulus; Surveys; System; T-Lymphocyte; TRPV1 gene; Testing; Therapeutic Intervention; Thinking; Tissues; Vanilloid; Work; adaptive immune response; base; cell behavior; cytokine; immunopathology; in vivo; interleukin-22; interleukin-23; intradermal injection; intravital microscopy; mechanical pressure; multi-photon; nerve supply; neuroregulation; new therapeutic target; novel; public health relevance; receptor; relating to nervous system; response; skin disorder; somatosensory; tissue repair

 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.

 描述（由申请人提供）：炎症性皮肤病，例如牛皮癣、特应性皮炎和接触性超敏反应，通常与令人不愉快的疼痛和瘙痒感有关，目前尚不清楚这些不适感是否以及在多大程度上可能在引发中发挥积极作用。并维持皮肤炎症，必须考虑到伤害性周围神经纤维有不同的亚群，它们传递不同的疼痛刺激，包括有害的热，在该项目的前期工作中，我们发现对特定疼痛刺激做出反应的感觉神经元子集对于小鼠皮肤中牛皮癣样皮炎的发展至关重要。细胞因子白细胞介素 (IL)-23 和 IL-17 的局部产生利用选择性伤害感受器消融的药理学和遗传模型，我们观察到特定的感觉神经元与皮肤驻留树突状细胞非常接近。 (DC)，对于 DC 产生 IL-23 至关重要，这是促进皮肤 T 细胞随后分泌 IL-17 所必需的。在这里，我们建议检验伤害感受器的皮肤躯体感觉在调节炎症中发挥积极作用的假设。通过控制组织驻留免疫细胞产生关键细胞因子来控制皮肤反应，我们的实验方法将使我们能够确定不同的疼痛感觉如何有助于调节先天性和适应性皮肤免疫系统的不同分支。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。为了检验我们的假设，我们提出了两个得到广泛初步数据支持的目标：目标 1：进行研究。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疼痛模式和驱动皮肤 1 型、2 型或 17 型反应的炎症模块之间的关系 目标 2. 描述调节的特征。我们将通过伤害感受器对树突状细胞进行表型分析并可视化树突状细胞响应皮肤神经调节的行为。