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Epidermal Nonpeptidergic Nerves Modulate Cutaneous Immunity

表皮非肽能神经调节皮肤免疫

基本信息

批准号：
10216987
负责人：
Kathryn Marie Albers
金额：
$ 53.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10216987
关键词：
Ablation Acute Afferent Neurons Agonist Allergic Disease Automobile Driving Candida albicans Cell Degranulation Cell physiology Cells Chronic Contact hypersensitivity Croton Cutaneous Data Dendritic Cells Dendritic cell activation Dermal Dermis Development Diphtheria Toxin Epidermis Event G-Protein-Coupled Receptors Genetic Goals Haptens Host Defense IL17 gene Immune Immune response Immunity Immunologic Tests Immunosuppression Individual Infection Infectious Skin Diseases Inflammation Inflammatory Innate Immune Response Interleukin-17 Interruption Irritants Lasers Link Mechanoreceptors Mediating Modeling Mus Nerve Neurogenic Inflammation Neuroimmune Neurons Oils Organ Pain Pathogenesis Pathway interactions Phenotype Primates Production Pruritus Resistance Sensory Skin Somatostatin Staphylococcus aureus Stimulus TRPV1 gene Testing Th2 Cells Touch sensation Work afferent nerve base cutaneous sensory neurons diphtheria toxin receptor extracellular gain of function immune function in vivo loss of function mast cell optogenetics pain sensation pathogen response single-cell RNA sequencing transcriptomics

项目摘要

Abstract The skin is a highly innervated organ and contains numerous sensory afferent neurons that respond to a diverse array of stimuli including touch, pruritogens (inducing itch) and noxious agents (inducing pain). There are also many skin-resident immune cells including dendritic cells and mast cells that make direct contact with sensory neurons. It has very recently become appreciated that cutaneous sensory neurons and skin-resident innate immune cells work synergistically to initiate local inflammation and host defense. We have previously shown that TRPV1+ neurons that sense pain are necessary and sufficient for cutaneous innate Type-17 inflammation and host defense against C. albicans. Thus, a neuron subset associated with painful stimuli is necessary and sufficient to drive a Type-17 immune response which is the optimal immune response against extracellular pathogens that can cause painful stimuli. We now propose to test the immunologic potential of nonpeptidergic sensory neurons are that can be divided based on single cell RNAseq into at least 3 subsets: NP1, NP2, and NP3. The overall goal of this proposal is to understand the unique contribution of individual subsets of nonpeptidergic sensory neurons to the modulation of skin immunity. Exploring this neuro- immune interaction will better define the cellular circuits driving inflammation and allow for the use of agonists/antagonists that target neuron subsets in order to modulate specific types of cutaneous immune responses without global immunosuppression. Specifically, we hypothesize that NP1 sensory nerves function to suppress mast cell activity. We further hypothesize that the NP2 and NP3 subsets that communicate itch sensation in response to pruritogens also participate in the development of Type-2 immune responses analogous to TRPV1+ neurons and Type-17 immune responses. The potential to modulate Th2 and mast cell function makes these pathways potential key for allergic disease pathogenesis.

摘要皮肤是一个高度神经支配的器官，含有大量的感觉传入神经元，对各种刺激做出反应，包括触摸、瘙痒(引起瘙痒)和有害刺激药物(引起疼痛)。还有许多皮肤驻留的免疫细胞，包括树突状细胞以及与感觉神经元直接接触的肥大细胞。它最近变成了认识到皮肤感觉神经元和皮肤固有免疫细胞起作用协同启动局部炎症和宿主防御。我们之前已经表明，感觉疼痛的TRPV1+神经元是皮肤先天17型的必要条件和充分条件白念珠菌的炎症和宿主防御。因此，与之相关联的神经元子集痛苦的刺激是驱动17型免疫反应的必要条件和充分条件，这是针对可能引起疼痛刺激的细胞外病原体的最佳免疫反应。我们现在建议测试非肽能感觉神经元的免疫潜力根据单细胞RNAseq被划分为至少3个子集：NP1、NP2和NP3。这个本提案的总体目标是了解以下各项的独特贡献非肽能感觉神经元对皮肤免疫的调节作用。探索这个神经- 免疫相互作用将更好地定义驱动炎症的细胞回路，并允许使用靶向神经元亚群的激动剂/拮抗剂以调节特定类型的没有全局免疫抑制的皮肤免疫反应。具体来说，我们假设 NP1感觉神经的功能是抑制肥大细胞的活动。我们进一步假设传递瘙痒感觉的NP2和NP3亚群也参与类似TRPV1+神经元的2型免疫反应的发展，并 17型免疫反应。调节Th2和肥大细胞功能的潜力使这些通路可能是过敏性疾病发病机制的关键。