Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue-specific transgenic mice, various itch models, behavior scoring, RNA sequencing, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice but upregulated skin protease-activated receptor 2 (PAR2) transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing transcription and activity. Coinjection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. In addition, IL-27 boosted transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuron–specific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL-27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade.

中文翻译：

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神经元 BST2：IL-27 驱动的瘙痒通路中与蛋白酶激活受体 2 一起的瘙痒介质

慢性瘙痒是一种常见且复杂的症状，通常与特应性皮炎 (AD) 等皮肤病相关。尽管 IL-27 与 AD 相关，但其在瘙痒中的作用和临床意义仍不清楚。我们试图使用组织特异性转基因小鼠、各种瘙痒模型、行为评分、RNA 测序和细胞因子/激酶阵列来研究 IL-27 在瘙痒中的功能。我们的研究结果表明，IL-27 受体在人类 AD 皮肤中过度表达。皮内注射 IL-27 未能直接诱导小鼠瘙痒，但上调皮​​肤蛋白酶激活受体 2 (PAR2) 转录物，这是瘙痒和 AD 的关键因素。IL-27 激活人类角质形成细胞，增加转录和活性。在小鼠体内同时注射 SLIGRL（PAR2 激动剂）和 IL-27 会加剧 PAR2 介导的瘙痒。此外，IL-27 增强了感觉神经元和角质形成细胞的转录。BST2 在 AD 皮肤中表达上调，将其注射到小鼠体内会引起瘙痒样反应。BST2 与人类和小鼠 AD 皮肤中的感觉神经分支共定位。感觉神经元释放 BST2，而感觉神经元特异性 BST2 敲除的小鼠表现出瘙痒反应减少。总的来说，这项研究提供了证据表明皮肤 IL-27/PAR2 和神经元 IL-27/BST2 轴与皮肤炎症和瘙痒有关。瘙痒症中神经元 BST2 的发现揭示了 BST2 在瘙痒级联中的作用。