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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

项目摘要皮肤作为一种保护性的物理屏障以及一种免疫器官，但也易患自身炎性疾病。皮肤的免疫力包括不同细胞类型之间的炎性细胞因子级联反应的发展，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导致宿主对细胞外病原体的防御，但这级联反应在诸如寻常性银屑病和化脓性汗腺炎的疾病中也是致病的。一已经描述了涉及IL-4和IL-13的类似级联用于防御寄生虫和特应性皮炎最近，人们认识到表达TRPV 1的皮肤神经元在神经细胞中起着重要的作用。在皮肤炎症中的专性作用，但确切的机制仍然未知。在过去的一个周期中，我们研究了TRPV 1表达的激活是否会影响TRPV 1的表达。神经元在没有任何组织损伤的情况下可能引发炎症。利用光遗传学，我们发现用激光对TRPV 1表达神经元进行多轮激活足以触发17型炎症，其依赖于感觉神经释放的神经肽CGRP 神经末梢和真皮树突细胞。宿主对表皮C.白色念珠菌和S. 金黄色葡萄球菌感染增加，17型炎症和宿主防御都延长通过神经反射弧超出刺激部位，提供区域预期免疫。的光遗传学刺激的时间精确性使我们能够询问TRPV 1的早期阶段，介导的神经炎症。在这个提议中，我们试图验证神经炎症由TRPV 1表达神经元触发，最初激活肥大细胞，导致免疫球蛋白聚集，细胞，然后允许从真皮树突状细胞产生CGRP依赖性IL-23。我们将我们还测试了TRPV 1表达神经元是否不仅触发炎症，这是维持持续炎症所需的反馈回路。最后，我们来看看，刺激TRPV 1表达神经元影响适应性免疫并足以触发Th 17 皮肤驻留记忆Th 17的分化和再激活。我们的期望是，充分描绘神经炎症通路，我们将获得发展的基本见解，先天性免疫反应，并允许潜在的治疗干预。此外，调制表达TRPV 1的神经元的适应性免疫将神经炎症与急性发作联系起来。已建立的17型自身免疫性疾病，如银屑病，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.