The neuropeptide neuromedin U promotes atopic dermatitis via stimulation of ILC2s

先天淋巴样细胞（ILCs）是屏障表面免疫反应的重要介质，可以引起组织保护性或有害的免疫反应。此外，神经元通过分泌神经肽，如神经素U (NMU)，成为组织中ILCs的调节剂。我们和其他人最近发表了胆碱能神经元通过神经素U受体1 （NMUR1）产生NMU来刺激ILC2s和2型免疫反应。过度的2型反应是特应性疾病的标志，如特应性皮炎、过敏性哮喘、花粉热和食物过敏，这些疾病在工业化国家已达到大流行的程度。然而，神经元因子（如NMU）如何引发特应性疾病，以及在皮肤炎症期间神经元如何与ILC2s相互作用，目前尚不清楚。利用最先进的遗传工具，这项建议及时地迈出了回答这些问题的第一步。预期的结果将对特应性疾病的预防和治疗靶向具有巨大的意义。特异性目的1：解剖NMU-NMUR1轴在特应性皮炎中的作用ILC2s在特应性疾病中的有害作用现在正在出现。现有数据提供了令人信服的证据，表明神经元、ILC2s和警报器是触发特应性皮炎皮肤炎症的组织特异性回路的一部分，但我们缺乏对分子细节的了解。我们的初步数据表明NMU-NMUR1在特应性皮炎中具有非冗余作用。现在，我们想了解NMU如何触发ILC2s促进特应性皮炎，ILC2s如何对NMU刺激做出反应，以及NMU如何与警报器和干扰素协同作用，这些已经与小鼠和人类的特应性皮炎有关。最后，我们的目标是分析NMU信号控制的ILC2s的整个转录网络。特异性目标2：探讨NMU+神经元和ILC2s的相互作用如何调节特应性皮炎。在健康和疾病中，神经元通过调节免疫细胞在形成器官功能的稳态中发挥什么作用是当今该领域突出的基础问题之一。我们的目的是研究NMU+神经元和ILC2s的相互作用如何促进特应性皮炎。为此，我们的目标是了解NMU+簇是如何组成的，它们如何促进与ILC2s的相互作用，以及它们在皮肤炎症期间如何变化。为了更直接地研究神经元的基因表达和功能，我们开发了优雅的遗传工具，使我们能够测量稳态和皮肤炎症期间神经元中的基因表达。最后，我们利用设计药物受体特异性地改变NMU+神经元的激活阈值。这组实验将使我们能够得出NMU+神经元如何调节特应性皮炎的结论。

Innate lymphoid cells (ILCs) are important mediators of immune responses at barrier surfaces and mount either tissue-protective or detrimental immune responses. In addition, neurons emerge as regulator of ILCs in tissues through secretion of neuropeptides, such as neuromedin U (NMU). We and others have recently published that cholinergic neurons produce NMU to stimulate ILC2s and type 2 immune responses through neuromedin U receptor 1 (NMUR1). Excessive type 2 responses are hallmarks of atopic diseases, such as atopic dermatitis, allergic asthma, hay fever and food allergy, which have reached pandemic proportions in industrialized countries. However, how neuronal factors, such as NMU trigger atopic disease and how neurons interact with ILC2s during skin inflammation is poorly understood. Using state-of-the-art genetic tools, this proposal takes the timely first steps in answering these questions. The anticipated results will carry tremendous implications for the prevention and therapeutic targeting of atopic diseases.Specific Aim 1: To dissect the role of the NMU-NMUR1 axis in atopic dermatitisThe detrimental role of ILC2s in atopic diseases is now emerging. Available data provide compelling evidence that neurons, ILC2s and alarmins are part of tissue-specific circuits that trigger skin inflammation in atopic dermatitis but we lack insights in the molecular details. Our preliminary data indicate a non-redundant role for NMU-NMUR1 in atopic dermatitis. Now, we want to understand how NMU triggers ILC2s to promote atopic dermatitis, how ILC2s react to NMU stimulation and how NMU acts in concert with alarmins and interferons, which have been already linked to atopic dermatitis in mice and humans. Finally, we aim to analyze the whole transcriptional network in ILC2s controlled by NMU signaling. Specific Aim 2: To interrogate how the interaction of NMU+ neurons and ILC2s regulates atopic dermatitis What role neurons play in shaping the homeostasis of organ function by regulating immune cells in health and disease is one of the outstanding, fundamental questions in the field today. We aim to investigate how the interaction of NMU+ neurons and ILC2s promotes atopic dermatitis. To this end, we aim to understand how NMU+ clusters are composed of, how they promote interactions with ILC2s and how they change during skin inflammation. In order to more directly investigate gene expression and function of neurons, we have developed elegant genetic tools, which allow us to measure gene expression in neurons in steady state and during skin inflammation. Finally, we employ designer drug receptors to specifically change the activation threshold of NMU+ neurons. This set of experiments will allow us to draw conclusion on how NMU+ neurons regulate atopic dermatitis.