The Role of IL-33 in Chronic Itch

项目总结 慢性瘙痒是一种使人虚弱的症状，严重限制生活质量，影响多达20%的人口。 尽管如此，目前还没有FDA批准的药物专门用于治疗慢性瘙痒。我们目前的情况 对慢性瘙痒病理生理学的理解在很大程度上源于对炎症性疾病的研究，如 特应性皮炎(即湿疹)。然而，在缺乏明显皮肤的情况下，慢性瘙痒是如何发生的 人们对炎症知之甚少。原因不明的慢性瘙痒症(CPUO)临床上没有这种明显的皮肤 炎症，占所有慢性瘙痒病例的40%，缺乏有效的治疗方法。不正当壁垒 由于皮肤干燥、老化所致的功能被认为是CPUO瘙痒的关键驱动因素，然而，什么可能是中介因素 这是未知的。尽管如此，我们的实验室已经将这种情况的认识放在了一系列的首要位置。 最新出版的书籍。 IL-33是角质形成细胞在损伤或应激时释放的一种“警报”。我们的初步研究表明，IL- 与健康对照组相比，CPUO患者血清中33水平升高。此外，最近的一项研究表明， 在一个总结了几个关键因素的小鼠模型中，IL-33是干性皮肤瘙痒发生所必需的 CPUO的各个方面。然而，IL-33促进瘙痒的机制以及这一过程是如何调控的 人们对此仍然知之甚少。IL-33是免疫细胞反应的有效诱导剂，然而，我们和其他人 发现IL-33可以直接激活感觉神经元。因此，在目标1中，我们将确定IL-33是否是一个关键的介体 利用我们培育的新型小鼠，研究干性皮肤瘙痒的直接上皮神经元轴。IL-33的活性为 蛋白水解酶的裂解作用显著增强。我们的初步数据表明，丝氨酸蛋白酶KLK7， 对屏障内稳态很重要，通过一种未知的机制促进慢性瘙痒。在目标2中，我们将 评价KLK7是否能裂解IL-33，增强IL-33的S致痒能力。我们的长期目标是确定 IL-33和KLK7是否为CPUO的治疗靶点。我们建议的总体目标是确定 IL-33和KLK7在促进干性皮肤瘙痒中的作用我们的中心假设是，IL-33代表着一种直接的 受KLK7调控的瘙痒上皮-神经元介质。这项提议的理由是，一旦它被 了解IL-33和KLK7如何促进干燥皮肤的瘙痒，这些机制可以被利用来创造有效的 以及治疗CPUO和其他与皮肤干燥相关的疾病的新疗法。

PROJECT SUMMARY Chronic itch is debilitating symptom that severely limits quality of life and affects up to 20% of the population. Despite this, there are no FDA-approved drugs specifically indicated for the treatment of chronic itch. Our current understanding of chronic itch pathophysiology largely derives from studying inflammatory disorders such as atopic dermatitis (i.e. eczema). However, how chronic itch arises in conditions that lack overt cutaneous inflammation is poorly understood. Chronic pruritus of unknown origin (CPUO) clinically lacks such overt skin inflammation, accounts for up to 40% of all chronic itch cases and lacks effective treatments. Improper barrier function due to dry, aging skin has been proposed as a key driving factor of itch in CPUO, yet what may mediate this is unknown. Notwithstanding this, our lab has brought recognition of this condition to the forefront in a series of recent publications. IL-33 is an `alarmin' released from keratinocytes upon damage or stress. Our preliminary studies show that IL- 33 is elevated in the sera of patients with CPUO compared to healthy controls. Further, a recent study showed that IL-33 is required for the development of dry skin itch in a murine model that recapitulates several of key aspects of CPUO. However, the mechanisms by which IL-33 promotes itch and how this process is regulated remains poorly understood. IL-33 is a potent inducer of immune cell responses, however, we and others have found that IL-33 can directly activate sensory neurons. Thus, in Aim 1, we will determine if IL-33 is a key mediator of a direct epithelial-neuronal axis in dry skin itch using novel mice we have generated. The activity of IL- 33 is dramatically enhanced upon cleavage by proteases. Our preliminary data suggest that the serine protease KLK7, important for barrier homeostasis, promotes chronic itch through an unknown mechanism. In Aim 2, we will evaluate if KLK7 cleaves IL-33, and enhances IL-33's capacity to induce itch. Our long-term goal is to determine whether IL-33 and KLK7 are therapeutic targets in CPUO. The overall objective of our proposal is to identify the role of IL-33 and KLK7 in promoting dry skin itch. Our central hypothesis is that IL-33 represents a direct epithelial-neuronal mediator of itch that is regulated by KLK7. The rationale for this proposal is that once it is understood how IL-33 and KLK7 promote itch in dry skin, these mechanisms can be harnessed to create effective and novel therapies for CPUO and other dry skin-related conditions.