Neuronal regulation of sinonasal Type 2 inflammation

鼻窦 2 型炎症的神经元调节

• 批准号: 10740468
• 负责人: De'Broski R Herbert
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740468
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Affect; Afferent Neurons; Allergens; Allergic; Allergic Disease; Allergic inflammation; Alternaria; Aspergillus fumigatus; Automobile Driving; Basal Cell; Behavior; Bone Marrow; Capsaicin; Cell Differentiation process; Cell Lineage; Cell secretion; Cells; Characteristics; Chimera organism; Chronic; Cre driver; Curiosities; Data; Development; Disease; Ensure; Eosinophilia; Epithelial Cells; Epithelium; Evaluation; Excision; Exposure to; Facial Pain; Feedback; Functional disorder; Genetic; Goals; Healthcare; Immune; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukins; Intranasal Administration; Knowledge; Liquid substance; Lymphoid Cell; Macrophage; Mediator; Modeling; Molecular; Mucous Membrane; Mucous body substance; Mus; Nasal Epithelium; Nasal cavity; Nerve; Neuroglia; Neuroimmune; Neurons; Neuropeptides; Nociceptors; Operative Surgical Procedures; Outcome; Patients; Peptide Initiation Factors; Population; Process; Proliferating; Proteins; Proteolysis; Quality of life; Regulation; Resistance; Role; Signal Transduction; Sneezing; Specialized Epithelial Cell; Structure of trigeminal ganglion; Substance P; TACR1 gene; TRPV channel; TRPV1 gene; Testing; Tissues; Transgenic Mice; Trigeminal System; Vanilloid; airway epithelium; analog; associated symptom; care burden; cell type; chronic rhinosinusitis; clinically relevant; cysteinyl-leukotriene; cytokine; cytotoxic; eosinophil; high reward; high risk; insight; loss of function; mouse model; new therapeutic target; novel; postmitotic; receptor; recruit; release factor; response; rhinosinusitis; single-cell RNA sequencing; stem cells; therapeutic target; transcriptome

Project Summary Chronic rhinosinusitis represents a significant healthcare burden, yet the cellular and molecular mechanisms driving disease are unclear in part, from a lack of clinically relevant mouse models. Allergic fungal rhinosinusitis (AFRS) is characterized by exacerbated sneezing, type 2 inflammatory response, eosinophilia and high numbers of specialized epithelial cells called sinonasal tuft cells (STCs) in response to fungal allergen exposure. It is currently not known how allergens are detected and inflammation is initiated in sinonasal mucosa. Trigeminal (TG) sensory neurons that innervate the respiratory epithelium sit in close apposition to STCs. TG neurons that express the Transient Receptor Potential Channel Vanilloid 1 (TRPV1) are required for sneezing, but it is not known if they become sensitized by allergen and progressively increase sneezing. To address these knowledge gaps, we have developed a mouse model of AFRS using chronic intranasal (i.n.) administration of a fungal allergen mix (FAM) that recapitulates all the cellular and cytokine-associated features of AFRS. Preliminary data show that ablation of intranasal TRPV1+ neurons, and perhaps other cell types, blocks STC expansion and eosinophil recruitment and reduces sneezing. Intranasal treatment of mice with the neuropeptide substance SP alone induces STC expansion and sneezing and cultured TG neurons exposed to fungal allergen secrete SP in and adaptive manner; showing greater secretion of SP when previously exposed to fungal allergen. Curiously, the adaptive increase in allergen-induced SP was lost in mice with a genetic deficiency in the alarmin cytokine interleukin (IL)-33. Taken together, we hypothesize that sinonasal TRPV1+ neurons respond to fungal allergens by releasing SP, which in turn, directs STC expansion from progenitor cells, leading to allergic inflammation, and excessive sneezing. We will test this hypothesis in two complementary, but independent aims. Aim 1 will identify the SP-responsive cells that promote STC expansion and allergic inflammation. This will be done in three sub-aims using transgenic mice that allow either gain (1A) or loss (1B) of function approach to either activate or ablate epithelial and immune cells receiving the SP signal and evaluate the cellular profile and sneezing behavior associated with those treatments. In 1C, we will perform single cell RNA sequencing in progenitor cells to establish how SP and fungal allergen instruct their differentiation into STC. Aim 2 seeks to define the neuron-specific contribution to fungal allergen-induced inflammatory responses and test whether selective loss of IL-33 responsive nociceptive neurons blocks allergic disease pathophysiology. In 2A we will use bone marrow chimeras of TRPV1+cre-DTR mice to determine the relative contribution of different TRPV1+ cell types to our previous findings. In 2B we will test whether mice with a selective loss of IL-33 responsiveness in nociceptive neurons are protected against excessive sneezing, STC expansion, and innate immune responses following one or more exposures to FAM.

项目概要 慢性鼻窦炎是一个重大的医疗负担，但细胞和分子机制 由于缺乏临床相关的小鼠模型，导致疾病的部分原因尚不清楚。过敏性真菌性鼻窦炎 (AFRS) 的特点是打喷嚏加剧、2 型炎症反应、嗜酸性粒细胞增多和大量 称为鼻鼻簇细胞（STC）的特殊上皮细胞响应真菌过敏原暴露。这是 目前尚不清楚如何检测过敏原以及如何在鼻窦粘膜中引发炎症。三叉神经 支配呼吸道上皮的感觉神经元 (TG) 与 STC 紧密相连。 TG 神经元 表示打喷嚏需要瞬时受体电位通道 Vanilloid 1 (TRPV1)，但事实并非如此 知道他们是否对过敏原过敏并逐渐增加打喷嚏。针对这些知识点 为了弥补这一差距，我们开发了一种 AFRS 小鼠模型，该模型使用慢性鼻内 (i.n.) 施用真菌 过敏原混合物 (FAM) 概括了 AFRS 的所有细胞和细胞因子相关特征。初步数据 研究表明，鼻内 TRPV1+ 神经元以及其他细胞类型的消融会阻止 STC 扩张， 嗜酸性粒细胞募集并减少打喷嚏。用神经肽物质SP对小鼠进行鼻内治疗 单独诱导 STC 扩增和打喷嚏，并且暴露于真菌过敏原的培养 TG 神经元在 和适应性方式；当先前暴露于真菌过敏原时，显示出更多的 SP 分泌。奇怪的是， 在警报素细胞因子遗传缺陷的小鼠中，过敏原诱导的 SP 的适应性增加消失了 白细胞介素（IL）-33。综上所述，我们假设鼻腔 TRPV1+ 神经元对真菌有反应 通过释放 SP 来消除过敏原，SP 反过来又指导祖细胞的 STC 扩增，导致过敏 炎症和过度打喷嚏。我们将在两个互补但独立的情况下检验这个假设 目标。目标 1 将鉴定促进 STC 扩张和过敏性炎症的 SP 反应细胞。 这将通过使用允许获得（1A）或丧失（1B）功能的转基因小鼠来完成三个子目标 激活或消融接收 SP 信号的上皮细胞和免疫细胞并评估细胞的方法 与这些治疗相关的个人资料和打喷嚏行为。在 1C 中，我们将进行单细胞 RNA 对祖细胞进行测序，以确定 SP 和真菌过敏原如何指导其分化为 STC。目的 2 试图定义神经元特异性对真菌过敏原诱导的炎症反应的贡献 并测试选择性丧失 IL-33 反应性伤害性神经元是否可以阻止过敏性疾病 病理生理学。在2A中，我们将使用TRPV1+cre-DTR小鼠的骨髓嵌合体来确定相对 不同 TRPV1+ 细胞类型对我们之前的发现的贡献。在 2B 中，我们将测试小鼠是否具有 伤害感受神经元中 IL-33 反应性的选择性丧失可防止过度打喷嚏，STC 一次或多次接触 FAM 后的扩张和先天免疫反应。