Keratinocytes contribute to normal cold and heat sensation

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.

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

“…The most abundant cell type in the epidermis are the keratinocytes, which both produce essential structural proteins and act as immune sentinels to discriminate between innocuous commensal microbes and harmful pathogens (27). Recent studies have demonstrated an additional important role for keratinocytes in mechanical, cold and heat detection via keratinocyte-sensory neuron purinergic signalling (28). Tolllike receptors (TLRs) are membrane-bound pattern recognition receptors (PRRs) expressed by keratinocytes and other cell types.…”

Nobel somatosensations and pain

“…TRPV3 found great attention in dermatology, a human gain-of-function mutation is in part responsible for the hyperkeratotic and mutilating Olmsted syndrome; TRPV3 plays roles in the control of hair growth and lipid secretion, in atopic dermatitis and pruritus [91,107]. However, by optogenetic inhibition of keratinocytes in mice, it was recently shown that stimulated ATP release from these cells contributes to behavioural heat, cold, and mechanosensitivity through neuronal P2X4 purinoceptor channels [109,147], and TRPV3 expression is essential for the heat-induced ATP release that is able to activate nearby DRG neurons in co-culture with keratinocytes [103].…”

A plant‐derived TRPV3 inhibitor suppresses pain and itch

“…Keratinocytes, the most abundant cell type in the epidermis, are located at the interface between the external environment and the internal milieu of the body (Huang et al, 2008). Recent works have demonstrated that keratinocytes are required for the behavioural and cellular mechanosensitivity, normal cold and heat sensation, and itch sensitization (Baumbauer et al, 2015;Moehring et al, 2018;Sadler et al, 2020;Szollosi et al, 2019). Keratinocytes can modulate and directly initiate nociceptive responses by eliciting action potential firing in nociceptive as well as tactile sensory afferents (Baumbauer et al, 2015).…”