Keratinocytes are required for normal cold and heat sensation

Abstract

Keratinocytes are the most abundant cell type in the epidermis, the most superficial layer of the skin. Historically, epidermal-innervating sensory neurons were thought to be the exclusive detectors and transmitters of environmental stimuli. However, recent work from our lab and others has demonstrated that keratinocytes are also critical for normal mechanotransduction and mechanically-evoked behavioral responses in mice. Here, we asked whether keratinocyte activity is also required for normal cold and heat sensation. We first observed cold-induced activity in mouse, rat, hibernating 13-lined ground squirrel, and human keratinocytes and determined that keratinocyte cold activity is conserved across mammalian species. Next, using transgenic mouse tissues and pharmacological tools, we determined that keratinocyte cold responses require the release of intracellular calcium through one or more unknown cold-sensitive proteins. This cold-induced keratinocyte activity is required for normal cold sensation as optogenetic inhibition of epidermal cells reduced reflexive behavioral responses to cold stimuli. Keratinocyte inhibition also decreased reflexive behavioral responses to heat stimuli. Lastly, we demonstrated that epidermal ATP-P2X4 signaling is required for normal cold and heat sensation. Based on these data and our previous findings, keratinocyte purinergic signaling is a modality-conserved amplification system that is required for normal somatosensation in vivo.