Exploiting growth factor modulation of alarmin release in atopic dermatitis

背景：特应性湿疹是世界上最常见的皮肤病，影响高达30%的儿童。这种疾病是由皮肤表面的细胞释放炎症信号引起的，这些信号引发过敏性免疫反应。这种过敏反应是引发瘙痒、红疹的关键，这可能影响患者的生活质量，扰乱儿童的注意力，儿童和父母的睡眠，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种细胞通路紧密交织在一起，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的释放对于湿疹的诱导至关重要;在日本小鼠模型中，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etokimab治疗湿疹的临床试验的支持。此外，我们实验室的初步数据还表明，湿疹常见细菌触发因子释放的IL-33受到涉及角质形成细胞生长因子EGF的第二种细胞途径的调节。在皮肤细胞中添加EGF可以抑制湿疹诱导性Alarmin IL-33的产生。相反，EGF的中和抗体促进IL-33的释放，促进过敏表型。宗旨和目标：这项研究旨在揭示正常皮肤和湿疹期间两种细胞途径（IL-33和EGF等生长因子）之间的复杂相互作用。我们还将评估已经用于临床实践并作用于这些细胞通路的药物的再利用，作为这种常见且通常使人衰弱的疾病的新疗法。这项工作计划涉及使用我们完善的人类皮肤细胞模型以及湿疹的临床前小鼠模型，一个在英国可用，另一个与我们的日本合作者一起使用，以评估各种药物在临床试验之前操纵这些途径的能力。我们将使用磷酸阵列以无偏见的方式询问关键通路，然后可以通过化学抑制剂和激活剂进行操纵。我们将研究这些途径中已知的候选物（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在细胞核中主动释放IL-33的重要伙伴（组蛋白和相关化学物质）。将通过评价皮肤评分、皮肤屏障功能和详细分析免疫应答来评估对湿疹的影响。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，绝大多数儿童湿疹的治疗方法保持不变，包括使用保湿霜和类固醇。我们相信，我们实验室的试点数据提供了两个开创性途径的线索，如果加以操纵，可能有助于开发新的治疗方法，特别是对于目前治疗有限且昂贵的严重疾病患者。这些研究也可能适用于其他过敏性疾病，其中IL-33是一个关键的球员，特别是过敏性哮喘，并可能有助于我们理解为什么一些治疗癌症（如西妥昔单抗）通常会导致严重的湿疹作为一个衰弱的副作用。

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.