The Role of IL-33 in Chronic Itch

项目摘要 慢性瘙痒是一种使人衰弱的症状，严重限制了生活质量，影响了多达20%的人口。 尽管如此，没有FDA批准的药物专门用于治疗慢性瘙痒。我们目前 对慢性瘙痒病理生理学的理解主要来源于研究炎症性疾病， 特应性皮炎（即湿疹）。然而，慢性瘙痒如何在缺乏明显皮肤刺激的情况下出现， 对炎症了解甚少。临床上不明原因的慢性瘙痒症（CPUO）缺乏这种明显的皮肤 炎症，占所有慢性瘙痒病例的40%，缺乏有效的治疗方法。屏障不当 由于干燥、老化皮肤的功能被认为是CPUO瘙痒的关键驱动因素，但什么可能介导 这是未知的。尽管如此，我们的实验室还是在一系列的研究中， 最近的出版物。 IL-33是在损伤或应激时从角质形成细胞释放的“alarmin”。我们的初步研究表明，IL- 与健康对照相比，CPUO患者血清中的33升高。此外，最近的一项研究表明， 在小鼠模型中，IL-33是皮肤干燥瘙痒发生所必需的， CPUO的一些方面。然而，IL-33促进瘙痒的机制以及这一过程是如何调节的， 仍然知之甚少。IL-33是免疫细胞反应的有效诱导剂，然而，我们和其他人已经发现， 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是否是关键介导因子 的直接上皮神经元轴在干燥皮肤瘙痒使用新的小鼠，我们已经产生。IL- 33的活性是 在被蛋白酶切割时显著增强。我们的初步数据表明丝氨酸蛋白酶KLK 7， 对屏障内稳态很重要，通过未知的机制促进慢性瘙痒。在目标2中，我们 评估KLK 7是否切割IL-33，并增强IL-33诱导瘙痒的能力。我们的长期目标是确定 IL-33和KLK 7是否是CPUO的治疗靶点。我们建议的总体目标是确定 IL-33和KLK 7在促进皮肤干燥瘙痒中的作用。我们的中心假设是IL-33代表了一种直接的 由KLK 7调节的瘙痒的上皮-神经元介质。这一建议的理由是，一旦 了解IL-33和KLK 7如何促进干燥皮肤的瘙痒，这些机制可以用来创造有效的 以及用于CPUO和其他干燥皮肤相关病症的新疗法。

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.