Defining the role of IL-18 in atopic dermatitis

定义 IL-18 在特应性皮炎中的作用

• 批准号: 10681016
• 负责人: Brian Kim
• 金额: $ 82.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681016
• 关键词: Acute; Adipose tissue; Adult; Allergic; Allergic inflammation; Atopic Dermatitis; Automobile Driving; Basophils; Behavior; Behavioral; Blood; Cell Separation; Cells; Child; Childhood; Chronic; Chronic Disease; Clinical; Data; Disease; Disease remission; Effector Cell; Etiology; Exhibits; Exposure to; Flare; Goals; Human; IL18 gene; Image; Immunofluorescence Immunologic; In Vitro; Inflammation; Interleukin-13; Interleukin-4; Interleukins; Knock-out; Knockout Mice; Lung; Lymphoid Cell; Maps; Measures; Mediating; Mediation; Mediator; Modeling; Mouse Strains; Mus; Neuroimmune; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Plasma; Production; Pruritus; Relapse; Role; Severity of illness; Signal Transduction; Skin; Skin Tissue; Source; System; Technology; Testing; Time; Tissues; Translating; Treatment Efficacy; United States; Visualization; conditional knockout; cytokine; design; human disease; in vivo; innovation; interleukin-18 binding protein; interleukin-18 receptor; mouse model; new therapeutic target; novel; novel therapeutic intervention; response; single-cell RNA sequencing; skin disorder; targeted treatment; therapeutic target; transcriptomics

ABSTRACT Atopic dermatitis (AD) is an increasingly common relapsing-remitting skin disease characterized by chronic allergic inflammation and itch. The etiology of AD is unknown, but type 2 cytokines, particularly interleukin (IL)- 4 and IL-13, are involved in driving AD and AD-like pathology, as demonstrated by the efficacy of therapies targeting these cytokines in human AD. Among type 2 cytokine producers, basophils and group 2 innate lymphoid cells (ILC2s) are dysregulated in human AD and are major sources of type 2 cytokines in mouse models of allergic inflammation, yet how these cells are triggered in AD and AD-like disease remain unresolved. Our recent single-cell RNA sequencing (scRNAseq) analysis identified high expression of IL-18 receptor (IL-18R, Il18r1) among skin ILC2s in comparison to ILC2s isolated from other tissues, and we further observed robust production of type 2 cytokines from IL-18-stimulated skin ILC2s, indicating that IL-18 is a candidate driver of type 2 cytokine production in AD-associated allergic skin inflammation. Basophils are also potently activated by IL-18 to produce type 2 cytokines, and our studies have demonstrated that basophils mediate acute itch flares in the context of AD-like disease, suggesting that IL-18 may mediate aspects of AD- related itch. Additionally, we find that IL-18 is elevated in both the skin and plasma of patients with moderate- to-severe AD, and that ILC2s and basophils exhibit unique activation profiles in human AD. Together, these data suggest that IL-18 mediates ILC2 and basophil functions to influence itch and AD pathogenesis. Thus, we hypothesize that IL-18 is a key regulator and potential therapeutic target in AD. In this project, we will determine how IL-18 influences basophil and ILC2 effector functions in the context of AD-associated inflammation and itch behavior. To do this, we will test several novel mouse strains in models of AD-like skin inflammation and translate these findings to human AD settings using innovative spatial transcriptomics approaches. We plan to test our hypothesis and accomplish our overall objective by pursuing three specific aims: 1. Test the contribution of IL-18 to skin ILC2 responses and AD-like disease. 2. Determine whether IL-18 activates basophils to trigger acute itch flares. 3. Examine the relationships between IL-18, ILC2s, and basophils in human AD by spatial transcriptomics. Understanding of how IL-18 contributes to the initiation and propagation of AD in mouse models and in human disease may advance new therapeutic approaches designed to ameliorate inflammation and itch in AD.

摘要 特应性皮炎（AD）是一种越来越常见的复发-缓解型皮肤病，其特征在于慢性炎症性皮炎。 过敏性炎症和瘙痒。AD的病因尚不清楚，但2型细胞因子，特别是白细胞介素（IL）- 4和IL-13参与驱动AD和AD样病理，如治疗的功效所证明的 在人类AD中靶向这些细胞因子。在2型细胞因子产生者中，嗜碱性粒细胞和2型先天性 淋巴样细胞（ILC 2）在人类AD中失调，并且是小鼠中2型细胞因子的主要来源。 过敏性炎症模型，但这些细胞如何在AD和AD样疾病中被触发仍然存在。 悬而未决我们最近的单细胞RNA测序（scRNAseq）分析确定了IL-18的高表达， 与从其他组织分离的ILC 2相比，我们进一步研究了皮肤ILC 2中IL-18受体（IL-18 R，IL-18 r1）的表达， 观察到IL-18刺激的皮肤ILC 2产生2型细胞因子，这表明IL-18是一种免疫调节剂。 AD相关过敏性皮肤炎症中2型细胞因子产生的候选驱动因素。嗜碱性粒细胞也是 被IL-18有效激活，产生2型细胞因子，我们的研究表明，嗜碱性粒细胞 在AD样疾病的背景下介导急性瘙痒发作，表明IL-18可能介导AD样疾病的某些方面。 痒相关此外，我们发现中度糖尿病患者的皮肤和血浆中IL-18均升高。 ILC 2和嗜碱性粒细胞在人类AD中表现出独特的激活特征。所有这些 数据提示IL-18介导ILC 2和嗜碱性粒细胞功能以影响瘙痒和AD发病机制。因此我们 假设IL-18是AD的关键调节因子和潜在治疗靶点。在这个项目中，我们将 确定IL-18如何影响嗜碱性粒细胞和ILC 2效应器功能， 炎症和瘙痒行为。为此，我们将在AD样皮肤模型中测试几种新的小鼠品系 炎症并使用创新的空间转录组学将这些发现转化为人类AD环境 接近。我们计划通过以下三个具体目标来验证我们的假设并实现我们的总体目标： 目标：1.测试IL-18对皮肤ILC 2反应和AD样疾病的贡献。2.确定IL-18是否 激活嗜碱性粒细胞引发急性瘙痒3.检查IL-18、ILC 2和 嗜碱性粒细胞在人类AD中的表达。了解IL-18如何有助于启动和 AD在小鼠模型和人类疾病中的传播可能会推进新的治疗方法 旨在改善AD的炎症和瘙痒。