The molecular basis of Interleukin-31 driven itch

项目总结 慢性瘙痒是许多疾病的症状，会导致压力、失眠和生活质量下降。 生活。除了精神上的损害，持续的抓挠还会通过以下方式加剧皮肤病 增强皮肤炎症，促进感染。然而，唯一具体的治疗选择是 抗组胺药物，这些药物大多无效。最近，细胞因子IL-31被确定为瘙痒的新靶点。 一项新完成的针对IL-31受体抗体(IL31RA)的II期临床试验显示， 特应性皮炎患者止痒效果观察。IL-31已被提议通过刺激一个子集的 皮肤中专门传递瘙痒信号的神经元，在小鼠身上的特征是一种 一种称为MAS相关G蛋白偶联受体A3(MRGPRA3)的蛋白质。然而，虽然我们已经证实， IL31RA阳性神经元确实存在，它们与MRGPRA3阳性神经元不重叠。然而，先生可能是 间接参与，因为我们有初步证据表明，IL-31诱导角质形成细胞释放激活的mrgpr 物质。因此，我们假设IL-31通过作用于一个新的、未表征的子集而直接引起瘙痒。 通过诱导角质形成细胞产生可激活mrgpr的瘙痒原。我们提出三个建议 一系列实验来验证我们的假设。首先，我们将评估IL-31是否会导致兴奋性的变化 和/或IL31RA阳性神经元的转录编程。这可能会导致长期、持久的 瘙痒感觉的增加，甚至可能比接触IL-31更持久。第二，我们将确定是否 角质形成细胞释放的激活MRGPR的物质是新发现的一类MRGPR的成员 配基。我们还将在MRGPR基因敲除小鼠中检测IL-31诱导的瘙痒。第三，我们将确定相对的 IL-31RA阳性神经元和角质形成细胞在IL-31通过敲除IL-31RA诱导的瘙痒中的作用 尤其是在神经元或上皮细胞中。这些将为未来的研究方向提供信息，并可能有助于选择 药物输送选项。我们提议的实验产生的数据将直接应用于 临床，作为第一个特定的止痒治疗选择，因为抗组胺是一种抗IL31RA抗体。一个 了解IL-31是如何发挥作用的，对于解释未来的临床结果、预测谁会和不会是至关重要的 从抗IL31RA治疗中受益，开发更具体的治疗方案，并识别其他疾病 这可能会通过靶向IL-31来治疗。

PROJECT SUMMARY Chronic itch is a symptom of many many diseases and causes stress, loss of sleep, and a decline in quality of life. In addition to the psychological damage, constant scratching physically exacerbates skin disease by enhancing skin inflammation and promoting infection. However, the only specific treatment options are antihistamines, which mostly are ineffective. Recently, the cytokine IL-31 was identified as a new target for itch. A newly-completed Phase II clinical trial of an antibody targeting the IL-31 receptor (IL31RA) showed remarkable efficacy in reducing itch in atopic dermatitis patients. IL-31 has been proposed to act by stimulating a subset of neurons in the skin that specifically transmits itch signals, and which is characterized in mice by expression of a protein called MAS-related G protein- coupled receptor A3 (Mrgpra3). However, while we have confirmed that Il31ra-positive neurons do exist, they do not overlap with Mrgpra3-positive neurons. However, Mrgprs may be involved indirectly, as we have preliminary evidence that IL-31 induces keratinocytes to release Mrgpr-activating substances. Thus, we hypothesize that IL-31 induces itch directly by acting on a new, uncharacterized subset of neurons, and indirectly by inducing keratinocytes to produce Mrgpr- activating pruritogens. We propose three sets of experiments to test our hypothesis. First, we will evaluate whether IL-31 induces changes in excitability and/or transcriptional programming in IL31RA-positive neurons. This could lead to long-term, persistent increases in itch sensation that may even outlast exposure to IL-31. Second, we will determine whether the substances released by keratinocytes that activate Mrgprs are members of a newly-identified class of Mrgpr ligands. We also will examine IL-31-induced itch in Mrgpr knockout mice. Third, we will determine the relative contributions of IL31RA-positive neurons and keratinocytes in IL-31-induced itch by knocking out IL31RA specifically in neurons or in epithelial cells. These will inform future research directions and may help to select drug delivery options. The data generated from our proposed experiments will have direct applications in the clinic, as the first specific anti-pruritic treatment option since antihistamines is an anti-IL31RA antibody. An understanding of how IL-31 works is essential to interpret future clinical results, to predict who will and will not benefit from anti-IL31RA therapy, to develop even more specific treatment options, and to identify other diseases that might be treated by targeting IL-31.