Defining the role of IL-18 in atopic dermatitis

摘要 特应性皮炎(AD)是一种日益常见的复发-缓解性皮肤病，其特征是慢性 过敏性炎症和瘙痒。阿尔茨海默病的病因尚不清楚，但2型细胞因子，特别是白细胞介素2- 4和IL-13参与了AD和AD样病理的驱动，如治疗效果所证明的那样 靶向人类阿尔茨海默病的这些细胞因子。在2型细胞因子产生者中，嗜碱性粒细胞和第2组先天 淋巴样细胞(ILC2s)在人类阿尔茨海默病(AD)中调节失调，是小鼠2型细胞因子的主要来源 变态反应性炎症模型，然而这些细胞如何在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)分析证实IL-18高表达 皮肤ILC2受体(IL-18R、IL18r1)与从其他组织分离的ILC2的比较 观察到IL-18刺激的皮肤ILC2强烈产生2型细胞因子，表明IL-18是一种 阿尔茨海默病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。嗜碱性细胞也是 被IL-18激活，产生2型细胞因子，我们的研究表明，嗜碱性粒细胞 在类AD疾病的背景下介导急性瘙痒发作，提示IL-18可能介导AD的某些方面- 相关的瘙痒。此外，我们还发现，在中度糖尿病患者的皮肤和血浆中，IL-18均升高。 到重度AD，ILC2和嗜碱性粒细胞在人类AD中表现出独特的激活特征。加在一起，这些 数据表明，IL-18介导ILC2和嗜碱性粒细胞功能，从而影响瘙痒和AD的发病。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AD相关环境中嗜碱粒细胞和ILC2效应器的功能 发炎和瘙痒行为。为了做到这一点，我们将在AD样皮肤模型中测试几个新的小鼠品系 利用创新的空间转录组学将这些发现转化为人类AD环境 接近了。我们计划通过追求三个具体的目标来检验我们的假设并实现我们的总体目标 目的：1.检测IL-18在皮肤ILC2反应和AD样病中的作用。2.确定IL-18是否 激活嗜碱性粒细胞以触发急性瘙痒发作。3.研究IL-18、ILC2和IL-18之间的关系 人类阿尔茨海默病中嗜碱性粒细胞的空间转录。了解IL-18如何参与启动和 阿尔茨海默病在小鼠模型和人类疾病中的传播可能推进新的治疗方法 旨在减轻AD时的炎症和瘙痒。

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.