Immune Functions of Cutaneous Nociceptors

项目摘要 皮肤的功能是一种保护性的物理屏障，也是一种免疫器官，保护 宿主不受病原体的侵袭，但也容易患自体炎症疾病。皮肤中的免疫涉及 炎性细胞因子在促进宿主的不同细胞类型之间的级联作用 防御性的，但在疾病中是致病的。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 CASCADE对寻常型牛皮癣和化脓性汗腺炎等疾病也有致病作用。一个 类似的涉及IL-4和IL-13的级联反应也被描述为用于抵御寄生虫和特应性 皮炎。最近，人们已经认识到，表达TRPV1的皮肤神经元在 在各种环境下的皮肤炎症中起主要作用，但确切的机制是 仍然不为人知。在这项资助的上一个周期中，我们探索了TRPV1表达的激活 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 发现用激光对表达TRPV1的神经元进行多轮激活足以 依赖于从感官释放的神经肽CGRP而触发的17型炎症 神经末梢和真皮树突状细胞。宿主对皮肤白念珠菌和S. 金黄色葡萄球菌感染增加，17型炎症和宿主防御都延长 通过神经反射弧线超出刺激部位，提供区域预期免疫。这个 光遗传刺激的时间精度使我们能够询问TRPV1的早期阶段- 介导性神经炎。在这项提议中，我们试图检验神经炎症的假设 由TRPV1表达的神经元触发最初激活肥大细胞导致免疫聚集性 细胞，然后允许依赖于CGRP的IL-23从真皮树突状细胞产生。我们会 还要测试TRPV1表达的神经元是否不仅会引发炎症，而且还会提供 维持持续炎症所需的反馈环。最后，我们检查是否 刺激TRPV1表达的神经元影响获得性免疫，并足以触发Th17 皮肤常驻记忆Th17的分化和再激活。我们的预期是通过更多 充分描绘神经炎性通路，我们将获得基本的洞察力 先天免疫反应，并允许潜在的治疗干预。此外，调制 表达TRPV1的神经元的获得性免疫将神经炎症与癫痫发作联系起来 已确诊的17型自身免疫性疾病，如牛皮癣以及潜在的 与慢性疼痛相关的自身免疫研究进展

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