Background

Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron–restricted activity of IL-33 is necessary for chronic itch remains poorly understood.

Objectives

We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models.

Methods

Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively.

Results

IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology.

Conclusions

These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch.

中文翻译：

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感觉神经元中的 IL-33 信号传导促进皮肤干燥瘙痒

背景

慢性瘙痒症或瘙痒很常见且使人衰弱，但导致慢性瘙痒的神经免疫机制才刚刚开始被阐明。最近的研究表明，IL-33 受体 (IL-33R) 由感觉神经元表达。然而，对于慢性瘙痒是否需要感觉神经元限制的 IL-33 活性仍然知之甚少。

目标

我们试图确定感觉神经元中的 IL-33 信号传导是否对 2 种不同的瘙痒疾病模型中慢性瘙痒的发展至关重要。

方法

在患有特应性皮炎 (AD) 和不明原因慢性瘙痒 (CPUO) 的患者中评估血浆 IL-33 水平。产生小鼠以有条件地从感觉神经元中删除IL-33R。在分别概括 AD 和 CPUO 的关键病理特征的小鼠模型中测试了神经元 IL-33R 信号传导对慢性瘙痒发展的贡献。

结果

IL-33 在 AD 和 CPUO 以及它们各自的小鼠模型中均升高。虽然神经元限制性 IL-33R 信号传导对于 AD 样疾病中的瘙痒是可有可无的，但它是在反映 CPUO 病理学关键方面的小鼠模型中发生皮肤干燥瘙痒所必需的。

结论

这些数据强调了 IL-33 在某些情况下可能是瘙痒的主要介质，具体取决于组织微环境。此外，这项研究提供了对针对慢性瘙痒的 IL-33 途径的未来治疗策略的见解。