Abstract
Keratinocytes are the most abundant cell type in the epidermis, the most superficial layer of skin. Historically, epidermal-innervating sensory neurons were thought to be the exclusive detectors and transmitters of environmental stimuli. However, recent work from our lab (Moehring et al., 2018) and others (Baumbauer et al., 2015) 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. Using calcium imaging, we determined that keratinocyte cold activity is conserved across mammalian species and requires the release of intracellular calcium through one or more unknown cold-sensitive proteins. Both epidermal cell optogenetic inhibition and interruption of ATP-P2X4 signaling reduced reflexive behavioral responses to cold and heat stimuli. 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.
Highlights
We and the team of Baumbauer, DeBerry, and Adelman et al reported that keratinocytes are required for normal innocuous and noxious mechanosensation; optogenetic inhibition of keratin14-expressing cells decreases mechanically-induced firing in Ab, Ad, and C fiber afferents (Baumbauer et al, 2015) and behavioral responses to hindpaw mechanical stimulation in naıve mice (Moehring et al, 2018)
2018), we observed decreased cold and heat sensitivity in wildtype mice after intraplantar injections of apyrase, an enzyme that catalyzes ATP hydrolysis, and in sensory-neuron specific P2X4 receptor knockout mice (P2X4cKO). These experiments are the first to demonstrate an in vivo requirement of keratinocyte activity for normal cold and heat sensation. Based on these and our previous studies (Moehring et al, 2018), we conclude that purinergic keratinocyte-to-sensory neuron signaling is a modality-conserved mechanism that serves as a critical amplifier for mechanical, cold, and heat sensation
Calcium transients were compared in keratinocytes isolated from mouse, rat, and hibernating 13-lined ground squirrel glabrous hindpaw skin and human hairy skin while external buffer temperature was decreased (~24 ̊C to 12 ̊C over 1 min; Figure 1A)
Summary
We and the team of Baumbauer, DeBerry, and Adelman et al reported that keratinocytes are required for normal innocuous and noxious mechanosensation; optogenetic inhibition of keratin14-expressing cells decreases mechanically-induced firing in Ab, Ad, and C fiber afferents (Baumbauer et al, 2015) and behavioral responses to hindpaw mechanical stimulation in naıve mice (Moehring et al, 2018) It is still unclear if keratinocyte activity is required for normal cold and heat sensation. 2018), we observed decreased cold and heat sensitivity in wildtype mice after intraplantar injections of apyrase, an enzyme that catalyzes ATP hydrolysis, and in sensory-neuron specific P2X4 receptor knockout mice (P2X4cKO) These experiments are the first to demonstrate an in vivo requirement of keratinocyte activity for normal cold and heat sensation. Based on these and our previous studies (Moehring et al, 2018), we conclude that purinergic keratinocyte-to-sensory neuron signaling is a modality-conserved mechanism that serves as a critical amplifier for mechanical, cold, and heat sensation
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