Keratinocyte PIEZO1 Mediates Touch Sensation and Touch Allodynia

Abstract

Despite the importance of touch sensation to our daily lives, our understanding of how we sense touch is still in its early stages. Keratinocytes, which make up 95% of the cells in the epidermis, respond to mechanical stimulation and contribute to mechanosensation by signaling to sensory neurons in the skin. It is unknown if this keratinocyte-to-sensory neuron signaling is altered in pain conditions associated with tactile hypersensitivity. Identification of the mechanoreceptors that enable keratinocytes to respond to mechanical stimuli may lead to the development of topical therapeutics for chronic touch pain. Here, we tested the hypothesis that keratinocytes contribute mechanical pain following tissue injury. We first examined if keratinocytes contribute to injury related pain by using optogenetics to selectively inhibit the keratinocytes of epidermal-specific Archaerhodopsin expressing mice treated with paclitaxel. We found that keratinocyte inhibition partially reversed paclitaxel induced touch pain. We next sought to determine the keratinocyte mechanotransducers which enable keratinocytes to respond to mechanical stimuli. We focused on PIEZO1, a mechanotransduction channel expressed in the skin. We found that mice with an epidermal deletion of PIEZO1 (PIEZO1cKO) were less responsive to a range of mechanical touch and pain assays. Furthermore, PIEZO1cKO mice were partially protected against the development of mechanical pain induced by Complete Freund's Adjuvant (CFA). Lastly, we examined the full complement of pain conditions in which keratinocyte PIEZO1 is sensitized by isolating keratinocytes from models of mechanical pain, including spared nerve injury, diabetes, sickle cell disease, and CFA. Using calcium imaging, we found that keratinocytes isolated from each injury condition were sensitized to activation by the PIEZO1 specific agonist Yoda1. Furthermore, primary human keratinocytes exposed to commonly used chemotherapeutics were sensitized to activation by Yoda1. Our data indicate that keratinocyte PIEZO1 mediates normal tactile sensation and may contribute to tactile pain following tissue injury. Grant support from NS040538 NS07071 NS108278.