Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity. Sci Transl Med 2024 Dec 11;16(777):eadn5629
Date
12/11/2024Pubmed ID
39661703DOI
10.1126/scitranslmed.adn5629Scopus ID
2-s2.0-85211969507 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
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.
Author List
Mikesell AR, Isaeva E, Schulte ML, Menzel AD, Sriram A, Prahl MM, Shin SM, Sadler KE, Yu H, Stucky CLAuthors
Olena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinSeung Min Shin PhD Assistant Professor in the Anesthesiology department at Medical College of Wisconsin
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Hongwei Yu MD Professor in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsHumans
Hyperalgesia
Ion Channels
Keratinocytes
Mice
Mice, Inbred C57BL
Paclitaxel
Signal Transduction
