Exploiting growth factor modulation of alarmin release in atopic dermatitis

背景：特应性湿疹是全世界最常见的皮肤病，影响多达30%的儿童。这种疾病是由皮肤表面的细胞释放炎症信号引发过敏免疫反应引起的。这种过敏反应对引发发痒、红疹至关重要，这会影响患者的生活质量，扰乱孩子的注意力，影响孩子和父母的睡眠，导致日常家庭生活的中断。我们实验室的新发现，其中一些最近发表在国际顶级过敏杂志上，发现皮肤细胞内的两条细胞通路密切交织在一起，对引发这种过敏性皮肤病至关重要。首先，我们发现炎症信号IL-33的释放对湿疹的诱导至关重要；在日本模拟儿童湿疹的小鼠模型中，我们可以通过阻断IL-33来预防疾病的发展。这一发现得到了抗il -33抗体依托基单抗治疗湿疹临床试验的支持。此外，我们实验室的试点数据还表明，由常见的湿疹细菌触发的IL-33的释放受第二种细胞途径的调节，该途径涉及角质细胞生长因子EGF。在皮肤细胞中添加EGF可抑制湿疹诱导报警素IL-33的产生。相反，EGF中和抗体促进IL-33的释放，促进过敏表型。目的和目的：本研究计划旨在揭示正常皮肤和湿疹期间两种细胞通路（IL-33和生长因子如EGF）之间复杂的相互作用。我们还将评估已经在临床实践中使用的药物的再利用，这些药物作用于这些细胞途径，作为这种常见且经常使人衰弱的疾病的新疗法。这项工作包括使用我们完善的人类皮肤细胞模型和临床前小鼠湿疹模型，一个在英国可用，另一个与我们的日本合作者合作，在临床试验之前评估各种药物操纵这些途径的能力。我们将使用磷酸阵列以公正的方式询问关键途径，然后可以通过化学抑制剂和激活剂进行操作。我们将研究这些途径中的已知候选物质（EGF和相关化学物质），以及最近通过我们的试点工作发现的那些从细胞核中主动释放IL-33的重要伙伴（组蛋白和相关化学物质）。对湿疹的影响将通过评估皮肤评分、皮肤屏障功能和详细分析免疫反应来评估。潜在的应用和益处：更好地了解疾病的分子和细胞基础是开发更有效疗法的核心。在过去的半个世纪里，绝大多数儿童的湿疹治疗方法一直保持不变，包括使用润肤霜和类固醇。我们相信，我们实验室的试点数据为两种生殖途径提供了线索，如果加以操纵，可能有助于开发新的治疗方法，特别是对目前治疗有限且昂贵的重症患者。这些研究也可能适用于IL-33起关键作用的其他过敏性疾病，特别是过敏性哮喘，并可能有助于我们理解为什么一些用于癌症治疗的疗法（例如西妥昔单抗）通常会导致严重的湿疹，这是一种使人衰弱的副作用。

Context: Atopic eczema is the most common skin disease worldwide, affecting up to 30% of children. The disease is caused by cells within the skin surface releasing inflammatory signals that initiate an allergic immune response. This allergic response is essential for triggering the itchy, red rash, which can impact of the patient's quality of life, disturbing the child's concentration, child and parent sleep, leading to disruption of daily family life. Novel findings from our laboratory, some of which has recently been published in a top international allergy journal, have found that two cellular pathways within skin cells are closely intertwined and essential for triggering this allergic skin disease. Firstly, we discovered that release of the inflammatory signal IL-33 is critical for the induction of eczema; in a Japanese mouse model that closely mimics childhood eczema, we can prevent disease developing by blocking IL-33. This finding is supported by the clinical trial of anti-IL-33 antibody etokimab in eczema. Additionally, pilot data from our laboratory has also shown that the release of IL-33 by a common bacterial trigger of eczema is regulated by a second cellular pathway involving the keratinocyte growth factor EGF. Adding EGF to skin cells inhibits the production of eczema-inducing alarmin IL-33. In contrast, neutralising antibodies to EGF promotes the release of IL-33, promoting the allergic phenotype. Aims and objectives: This research proposal aims to unravel the intricate interaction between two cellular pathways (IL-33 and growth factors such as EGF) in normal skin and during eczema. We will also evaluate the repurposing of drugs which are already used in clinical practice and which act on these cellular pathways, as novel therapies for this common and often debilitating disease. This program of work involves using our well established human skin cell model alongside preclinical mouse models of eczema, one available in the UK and the other with our Japanese collaborators, to evaluate the ability of various drugs to manipulate these pathways, prior to clinical trials. We will use phospho-arrays to interrogate key pathways in an unbiased way, which can then be manipulated by chemical inhibitors and activators. We will examine known candidates within these pathways (EGF and related chemicals), as well as those recently discovered through our pilot work to be essential partners in active release of IL-33 from the nucleus of the cell (histone and related chemicals). Impact on eczema will be assessed by evaluating skin scores, skin barrier function and detailed analysis of the immune response. Potential applications and benefits: Better understanding of the molecular and cellular basis of diseases is at the heart of developing more effective therapies. The treatment of eczema for the vast majority of children has remained unchanged over the last half century and involves application of moisturisers and steroids. We believe that pilot data from our laboratory provides clues to two seminal pathways, which if manipulated may aid in the development of new treatments, particularly for patients with severe disease where treatments are currently limited and expensive. These investigations may also be applicable to other allergic diseases where IL-33 is a key player, particularly allergic asthma, and may help in our understanding of why some therapies used in cancer treatment (e.g. cetuximab) commonly cause bad eczema as a debilitating side-effect.