Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity

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.