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Immune Functions of Cutaneous Nociceptors

皮肤伤害感受器的免疫功能

基本信息

批准号：
10671716
负责人：
Daniel H Kaplan
金额：
$ 50.61万
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：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671716
关键词：
Ablation Affect Atopic Dermatitis Autoimmune Autoimmune Diseases Autoimmunity Candida albicans Cell Degranulation Cell model Cells Cellularity Chronic small plaque psoriasis Complex Regional Pain Syndromes Contact hypersensitivity Cutaneous Data Dendritic Cells Dendritic cell activation Dermal Dermis Development Disease Feedback Flare Genetic Goals Grant Hidradenitis Hidradenitis Suppurativa Host Defense IL17 gene Imiquimod Immune Immunity Immunologics Infection Inflammation Inflammatory Innate Immune Response Interleukin-1 beta Interleukin-13 Interleukin-4 Interleukin-6 Ion Channel Irritant Dermatitis Kinetics Lasers Light Link Maintenance Mediating Memory Modeling Monitor Mus Nerve Neurons Neuropeptides Nociceptors Organ Pain Papain Papillary Parasites Pathogenicity Pathway interactions Patients Play Production Psoriasis Pyroglyphidae Reflex action Role Site Skin Staphylococcus aureus infection Stimulus T cell response T-Lymphocyte TRPV1 gene Testing Therapeutic Intervention Time Tissues Work adaptive immunity afferent nerve autoinflammatory diseases cell type chemokine chronic pain cutaneous sensory neurons cytokine designer receptors exclusively activated by designer drugs expectation extracellular immune function insight interleukin-23 mast cell mouse model neuroinflammation optogenetics pathogen response skin disorder

项目摘要

Project Summary The skin functions as a protective physical barrier as well as an immunologic organ that protects the host from pathogens but is also subject to autoinflammatory disease. Immunity in the skin involves the development of inflammatory cytokine cascades between different cell types that both promote host defense but are pathogenic in disease. For example, IL-23 from dermal dendritic cells drives production of IL-17 from T cells resulting inn host defense against extracellular pathogens but this cascade is also pathogenic in diseases such as psoriasis vulgaris and hidradenitis suppurative. A similar cascade involving IL-4 and IL-13 has been described for defense against parasites and atopic dermatitis. Recently, it has become appreciated that TRPV1-expressing cutaneous neurons play an obligate role in cutaneous inflammation across a wide variety of contexts, but the exact mechanism remains unknown. In the past cycle of this grant we explored whether activation of TRPV1-expressing neurons in the absence of any tissue damage could trigger inflammation. Using optogenetics, we found that multiple rounds of activation of TRPV1-expressing neurons with laser light was sufficient to trigger Type-17 inflammation which was dependent on the neuropeptide CGRP released from sensory nerve terminals and dermal dendritic cells. Host defense against epicutaneous C. albicans and S. aureus infection was augmented, and both the Type-17 inflammation and host defense extended beyond the site of stimulation through a nerve reflex arc providing regional anticipatory immunity. The temporal precision of optogenetic stimulation allows us to interrogate the early stages of TRPV1- mediated neuroinflammation. In this proposal we seek to test the hypothesis that neuroinflammation triggered by TRPV1-expressing neurons initially activates mast cells resulting in clustering of immune cells which then allows for CGRP-dependent production of IL-23 from dermal dendritic cells. We will also test whether TRPV1-expressing neurons not only trigger inflammation but also provide a positive feed-back loop that is required to maintain ongoing inflammation. Finally, we examine whether stimulation of TRPV1-expressing neurons affect adaptive immunity and is sufficient to trigger Th17 differentiation and reactivation of cutaneous resident memory Th17. Our expectation is that by more fully delineating neuroinflammatory pathways, we will obtain basic insight into the development of innate immune responses and allow for potential therapeutic intervention. Moreover, modulation of adaptive immunity by TRPV1-expressing neurons would link neuroinflammation with flares in established Type-17 autoimmune diseases such as psoriasis as well as potentially with the development of autoimmunity associated with chronic pain

项目概要皮肤充当保护性物理屏障以及保护皮肤的免疫器官。宿主免受病原体侵害，但也易患自身炎症性疾病。皮肤的免疫力涉及不同细胞类型之间炎症细胞因子级联的发展，都促进宿主防御但在疾病中致病。例如，来自真皮树突状细胞的 IL-23 驱动 T 细胞产生 IL-17，导致宿主防御细胞外病原体，但这级联还在寻常型牛皮癣和化脓性汗腺炎等疾病中致病。一个涉及 IL-4 和 IL-13 的类似级联已被描述用于防御寄生虫和特应性皮炎。最近，人们认识到表达 TRPV1 的皮肤神经元在在多种情况下皮肤炎症中都发挥着重要作用，但确切的机制仍然未知。在本次资助的上一个周期中，我们探索了 TRPV1 表达的激活是否在没有任何组织损伤的情况下，神经元可能会引发炎症。利用光遗传学，我们发现用激光多轮激活表达 TRPV1 的神经元足以触发 17 型炎症，该炎症依赖于感觉神经释放的神经肽 CGRP 神经末梢和真皮树突状细胞。宿主对表皮白色念珠菌和葡萄球菌的防御金黄色葡萄球菌感染增强，17 型炎症和宿主防御均延长通过神经反射弧超越刺激部位，提供区域预期免疫。这光遗传学刺激的时间精度使我们能够探究TRPV1-的早期阶段介导的神经炎症。在本提案中，我们试图检验以下假设：神经炎症由表达 TRPV1 的神经元触发，最初激活肥大细胞，导致免疫聚集然后，真皮树突细胞可以依赖 CGRP 产生 IL-23。我们将还测试表达 TRPV1 的神经元是否不仅引发炎症，而且还提供积极的维持持续炎症所需的反馈回路。最后，我们检查是否刺激表达 TRPV1 的神经元会影响适应性免疫并足以触发 Th17 皮肤常驻记忆Th17的分化和重新激活。我们的期望是通过更多充分描绘神经炎症途径，我们将获得对神经炎症发展的基本了解先天免疫反应并允许潜在的治疗干预。此外，调制表达 TRPV1 的神经元的适应性免疫将神经炎症与炎症联系起来已确定的 17 型自身免疫性疾病，例如牛皮癣以及潜在的与慢性疼痛相关的自身免疫的发展

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optogenetic inhibition of the colon epithelium reduces hypersensitivity in a mouse model of inflammatory bowel disease.

DOI：
10.1097/j.pain.0000000000002110
发表时间：
2021-04-01
期刊：
Pain
影响因子：
7.4
作者：
Najjar SA;Ejoh LL;Loeza-Alcocer E;Edwards BS;Smith-Edwards KM;Epouhe AY;Gold MS;Davis BM;Albers KM
通讯作者：
Albers KM

Neuronal Regulation of Cutaneous Immunity.