LANGERHANS CELLS AND NERVES: BIDIRECTIONAL SIGNALING

本申请的总体目标是评估和定义表皮朗格汉斯细胞（LC）和神经之间的双向信号传导。这项工作基于在初始资助期进行的以下观察：（1）LC与含降钙素基因相关肽（CGRP）的神经在解剖学上相关，（2）CGRP调节LC功能，（3）LC表达几种其他神经肽的受体，以及β-肾上腺素能受体，并且这些激动剂中的一些调节LC功能的方面，包括细胞因子表达和抗原呈递功能，以及（4）LC能够产生神经营养因子。因此，我们假设，双向信号发生在神经和LC之间，神经通过产生神经源性信号影响LC，而LC通过产生神经营养因子影响神经细胞。这种信号传导允许神经元调节免疫功能，并可能促进神经和LC之间促进这种功能调节的密切关联的形成。在目的1中，我们将通过检查LC对神经肽和神经递质的反应（对细胞因子表达、共刺激分子表达和抗原呈递的影响）和神经营养因子的产生来检验该假设。补充的体内实验将测试神经肽和神经递质在诱导和激发免疫中的生理重要性。 细胞因子缺陷（“敲除”）小鼠将用于测试某些细胞因子在神经因子效应中的参与。目的二研究原代神经元和神经肽对LC细胞迁移的影响。相反，我们将研究由神经细胞释放的诱导LC向神经细胞迁移的因子。拟议的研究将确定神经系统和免疫系统之间相互作用的重要位点。所获得的结果可以更好地了解神经系统如何影响皮肤内的免疫力，以及皮肤中神经系统和免疫系统之间的联系是如何形成的。这些研究可能会导致目前无法预见的新的治疗方法来治疗免疫紊乱，从牛皮癣到皮肤癌。

The overall goal of this application is to evaluate and define the bi- directional signaling between epidermal Langerhans cells (LC) and nerves This work is based on the following observations made in the initial funding period: (1) LC are anatomically-associated with calcitonin gene-related peptide (CGRP)-containing nerves, (2) CGRP regulates LC function, (3) LC express receptors for several other neuropeptides, as well as beta-adrenergic receptors, and some of these agonists regulate aspects of LC function including cytokine expression and antigen presenting function, and (4) LC are capable of producing neurotrophins. Thus, we hypothesize that bidirectional signaling occurs between nerves and LC with nerves influencing LC by production of neuron-derived signals while LC influence nerve cells by production of neurotrophins. This signaling allows regulation of immune function by neurons and may promote the formulation of the close association between nerves and LC that promotes this functional regulation. In Aim 1, we will test this hypothesis by examining LC for responses to neuropeptides and neuro-transmitters (effects on cytokine expression, co- stimulatory molecule expression and antigen presentation) and production of neurotrophins. Complementary in vivo experiments will test the physiological importance of neuropeptides and neurotransmitters in both induction and elicitation of immunity. Cytokine-deficient ("knock-out") mice will be used to test the involvement of certain cytokines in neural factor effects. In Aim 2, we will study the influence of primary neurons and neuropeptides on the migration of LC cells. Conversely, we will study the factors released by nerve cells that induce migration of LC towards nerve cells. The proposed studies will define an important locus of interaction between the nervous system and the immune system. The results obtained may provide a greater understanding of how the nervous system influences immunity within the skin, and how the association between the neural and immune systems in the skin is formed. These studies may lead to currently unforseen new therapeutic approaches to treat immunologic derangements, ranging form psoriasis to skin cancer.