Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy. We found that keratinocyte inhibition by either optogenetic or chemogenetic methods largely alleviated paclitaxel-induced mechanical hypersensitivity across acute and persistent time points from 2 days through 3 weeks. Furthermore, we found that paclitaxel exposure sensitized mouse and human keratinocytes to mechanical stimulation and enhanced currents of PIEZO1, a mechanosensitive channel highly expressed in keratinocytes. Deletion of PIEZO1 from keratinocytes alleviated paclitaxel-induced mechanical hypersensitivity in mice. These findings suggest that nonneuronal cutaneous cells contribute substantially to neuropathic pain and pave the way for the development of new pain relief strategies that target epidermal keratinocytes and PIEZO1.

中文翻译：

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角质形成细胞活性增加和 PIEZO1 信号传导导致紫杉醇诱导的机械超敏反应


最近的研究表明，表皮角质形成细胞对正常的触觉至关重要。然而，尚不清楚角质形成细胞是否会导致组织损伤后触摸诱发的疼痛和超敏反应。在这里，我们使用紫杉醇治疗的小鼠模型来确定角质形成细胞活性在多大程度上导致化疗伴随的严重神经性疼痛。我们发现，通过光遗传学或化学遗传学方法抑制角质形成细胞在 2 天至 3 周的急性和持续时间点在很大程度上减轻了紫杉醇诱导的机械超敏反应。此外，我们发现紫杉醇暴露使小鼠和人角质形成细胞对机械刺激敏感，并增强了 PIEZO1 的电流，PIEZO1 是一种在角质形成细胞中高度表达的机械敏感通道。从角质形成细胞中缺失 PIEZO1 减轻了紫杉醇诱导的小鼠机械超敏反应。这些发现表明，非神经元皮肤细胞对神经性疼痛有很大贡献，并为开发针对表皮角质形成细胞和 PIEZO1 的新疼痛缓解策略铺平了道路。