Role of nociceptive sensory neuron/mast cell interactions in cutaneous allergic inflammation

伤害性感觉神经元/肥大细胞相互作用在皮肤过敏性炎症中的作用

基本信息

批准号：
9922209
负责人：
Stephen Joseph Galli
金额：
$ 48.17万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922209
关键词：
3-Dimensional Affect Afferent Neurons Affinity Allergic inflammation Antibodies Antigens Atopic Dermatitis Brain CD4 Positive T Lymphocytes Cell Communication Cells Cellular Structures Child Chronic Chymase Complex Cutaneous Dangerousness Dermal Dermatitis Dermatophagoides farinae Dermis Development Disease Dyes Eczema Environment Epidermis Equilibrium Etiology Exhibits Exposure to Family Flow Cytometry Fluorescence G-Protein-Coupled Receptors Gene Expression Gene Expression Profile Genetic Health Homeostasis Human Hypersensitivity IgE IgE Receptors IgG1 Immune Immunity Immunologics Impairment Incidence Inflammation Inflammatory Lesion Measures Mediator of activation protein Microscopic Modeling Molecular Mus Nerve Fibers Neuroimmune Neurons Neuropeptide Receptor Neuropeptides Nociception Nociceptors Organ Paraffin Embedding Pathogenicity Pathologic Pathology Patients Peptide Hydrolases Permeability Play Population Production Pruritus Relapse Role Serum Signal Pathway Signal Transduction Skin Social Impacts Spinal Cord Staphylococcal Enterotoxin B Stimulus Structural Protein Structure Substance P Substance P Receptor T-Lymphocyte TAC1 gene TRPV1 gene Testing Time Water afferent nerve base claudin-1 protein cost cytokine draining lymph node experimental study filaggrin imaging approach innovation insight mast cell mouse model new therapeutic target receptor response skin barrier skin disorder skin lesion skin organogenesis uptake

项目摘要

Project Summary/Abstract Atopic dermatitis (AD) is a chronic relapsing inflammatory disease of the skin, characterized by pruritus (severe itching of the skin), eczema, and hypersensitivity to innocuous environmental substances, which affects 10- 20% of children worldwide. The etiology of AD is incompletely understood, but various types of immune or structural cells and multiple cell signaling pathways are thought to contribute to the development of skin lesions and immunological abnormalities in AD. The skin is a complex organ containing a large population of mast cells (MCs) and innervated by an intricate network of abundant sensory nerve fibers, including “nociceptors” – sensory nerves that are activated by harmful or potentially dangerous stimuli. Recent findings suggest that subtypes of nociceptive sensory neurons, by importantly influencing specialized immune cells, can regulate the development of both protective and pathogenic responses. Other recent studies have shown that mouse skin MCs exhibit strong expression of genes encoding receptors in the Mas-related G protein-coupled receptors (MRGPR) family (e.g., Mrgprb2: the receptor for the substance P [SP] in the mouse), through which MCs might uniquely interact with nociceptors. The central hypothesis of this project is that interactions between Trpv1+, Tac1+ (i.e., SP-producing) nociceptors and Mrgprb2+ MCs play a critical role in the development of the skin pathology and immunological abnormalities associated with type 2 skin inflammation. This hypothesis is based on the following preliminary findings: (1) TRPV1 gene expression is increased in the skin of AD patients. (2-4) Using a mouse model of AD, in which epicutaneous exposure to Dermatophagoides farinae extract (Der f) and staphylococcal enterotoxin B (SEB) induces a dermatitis whose skin pathology and gene expression pattern are similar to those in human AD, we found that: (2) Trpv1+ nociceptors and MCs, as well as expression of the Tac1 gene (encoding the precursor for SP), are required for dysregulation of claudin 1 structure, development of AD-like skin lesions, and production of Der f-specific IgG1 and IgE; (3) dermal MCs physically interact with skin SP+ nociceptors; and (4) MCs and Mrgprb2 are required for SP-induced skin inflammation. We now wish to extend these observations and explore their translational relevance by using state-of-the-art genetic and cell transfer studies in mice to understand the mechanisms of nociceptor/MC cross-talk in the development of AD skin pathology, impaired barrier function, and immunological abnormalities, and to use innovative imaging approaches to analyze and compare nociceptor/MC interactions in lesional skin of mice and in humans with AD. We think that the proposed studies will provide new insights into skin neuro-immune interactions that can influence type 2 skin inflammation, particularly those reflecting interactions between SP-producing peptidergic nociceptors and MCs, both in a mouse model of AD and in lesional skin of patients with AD. Accordingly, our findings have the potential to identify new therapeutic targets for treating AD and perhaps other type 2 skin disorders.

项目概要/摘要特应性皮炎（AD）是一种慢性复发性皮肤炎症性疾病，以瘙痒（严重瘙痒）为特征。皮肤瘙痒）、湿疹和对无害环境物质过敏，影响 10- 全世界 20% 的儿童 AD 的病因尚不完全清楚，但与各种类型的免疫或疾病有关。结构细胞和多种细胞信号传导途径被认为有助于皮肤病变的发展 AD 中的免疫学异常皮肤是一个复杂的器官，含有大量的肥大细胞。细胞（MC）并由丰富的感觉神经纤维组成的复杂网络支配，包括“伤害感受器” - 最近的研究结果表明，有害或潜在危险的刺激会激活感觉神经。伤害性感觉神经元的亚型通过严重影响专门的免疫细胞，可以调节最近的其他研究表明，小鼠皮肤会产生保护性和致病性反应。 MC 在 Mas 相关 G 蛋白偶联受体中表现出编码受体的基因的强烈表达 (MRGPR) 家族（例如，Mrgprb2：小鼠体内 P 物质 [SP] 的受体），通过该家族，MC 可以该项目的中心假设是 Trpv1+ 与伤害感受器之间的相互作用。 Tac1+（即产生 SP）伤害感受器和 Mrgprb2+ MC 在皮肤发育中发挥着关键作用该假设是基于与 2 型皮肤炎症相关的病理学和免疫学异常。初步研究结果如下： (1) AD 患者皮肤中 TRPV1 基因表达增加 (2-4)。使用 AD 小鼠模型，其中表皮暴露于粉尘螨提取物 (Der f) 和金黄色葡萄球菌肠毒素 B (SEB) 诱发皮炎，其皮肤病理学和基因表达模式与人类 AD 相似，我们发现：（2）Trpv1+ 伤害感受器和 MC，以及 Tac1 基因（编码 SP 的前体）是密蛋白 1 结构失调、发育所必需的 AD 样皮肤病变的发生以及 Der f 特异性 IgG1 和 IgE 的产生 (3) 真皮 MC 与皮肤发生物理相互作用；皮肤 SP+ 伤害感受器；(4) MC 和 Mrgprb2 是 SP 引起的皮肤炎症所必需的。通过使用最先进的遗传和细胞技术来扩展这些观察结果并探索其转化相关性小鼠转移研究，以了解伤害感受器/MC 串扰在 AD 发展中的机制皮肤病理学、屏障功能受损和免疫异常，并使用创新成像分析和比较小鼠和人类病变皮肤中伤害感受器/MC相互作用的方法我们认为拟议的研究将为皮肤神经免疫相互作用提供新的见解。影响 2 型皮肤炎症，特别是那些反映产生 SP 的肽能细胞之间相互作用的炎症 AD 小鼠模型和 AD 患者病变皮肤中的伤害感受器和 MC。研究结果有可能确定治疗 AD 和其他 2 型皮肤的新治疗靶点失调。