Exploiting growth factor modulation of alarmin release in atopic dermatitis

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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.