Intra‐epidermal nerve endings progress within keratinocyte cytoplasmic tunnels in normal human skin

Abstract

Intra‐epidermal nerve endings, responsible for cutaneous perception of temperature, pain and itch, are conventionally described as passing freely between keratinocytes, from the basal to the granular layers of the epidermis. However, the recent discovery of keratinocyte contribution to cutaneous nociception implies that their anatomical relationships are much more intimate than what has been described so far. By studying human skin biopsies in confocal laser scanning microscopy, we show that intra‐epidermal nerve endings are not only closely apposed to keratinocytes, but can also be enwrapped by keratinocyte cytoplasms over their entire circumference and thus progress within keratinocyte tunnels. As keratinocytes must activate intra‐epidermal nerve endings to transduce nociceptive information, these findings may help understanding the interactions between the keratinocytes and nervous system. The discovery of these nerve portions progressing in keratinocyte tunnels is a strong argument to consider that contacts between epidermal keratinocytes and intra‐epidermal nerve endings are not incidental and argue for the existence of specific and rapid paracrine communication from keratinocytes to sensory neurons.

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

“…FNE portions can even progress in keratinocyte cytoplasmic tunnels. 61 Those tunnels have been described to potentiate the nociceptive function of FNEs in drosophila larvae, 62 according to a mechanism that remains to be determined. But they could constitute a privileged site for specific and rapid paracrine communication from keratinocytes to sensory neurons.…”

“…Consequently, the term “free nerve ending” is no longer relevant, because nerves are not “free” but connected to keratinocytes. FNE portions can even progress in keratinocyte cytoplasmic tunnels 61 . Those tunnels have been described to potentiate the nociceptive function of FNEs in drosophila larvae , 62 according to a mechanism that remains to be determined.…”

Re‐innervation of human skin by rat dorsal root ganglia permits to study interactions between sensory nerve fibres and native human dermal mast cells ex vivo

“…Given that skin mast cells are among the key interaction partners of sensory NFs 3,4 (s1, s6), we have asked whether this rDRG re‐innervation model also permits to interrogate NF‐mast cell interactions in human skin ex vivo. Here, we present preliminary evidence that this is indeed the case (Figure 1A) and call attention to a striking, previously unreported mast cell–associated skin re‐innervation phenomenon that underscores the importance of mast cell‐NF interactions in human skin in health and disease 2,4,5 (s6).…”

“…Remarkably, as recently reported in this journal, rat sensory nerve fibres (NFs) directly interact with human epidermal keratinocytes ex vivo, which enwrap the free nerve endings within their cytoplasm, thereby creating intracellular tunnels and possibly communicating via neurosecretory vesicles 2 . Given that skin mast cells are among the key interaction partners of sensory NFs 3,4 (s1, s6), we have asked whether this rDRG re‐innervation model also permits to interrogate NF‐mast cell interactions in human skin ex vivo.…”

“…Remarkably, as recently reported in this journal, rat sensory nerve fibres (NFs) directly interact with human epidermal keratinocytes ex vivo, which enwrap the free nerve endings within their cytoplasm, thereby creating intracellular tunnels and possibly communicating via neurosecretory vesicles. 2 Given that skin mast cells are among the key interaction partners of sensory NFs 3,4 (s1, s6), we have asked whether this rDRG re-innervation model also permits to interrogate NF-mast cell interactions in human skin ex vivo. Here, we present preliminary evidence that this is indeed the case (Figure 1A) and call attention to a striking, previously unreported mast cell-associated skin re-innervation phenomenon that underscores the importance of mast cell-NF interactions in human skin in health and disease 2,4,5 (s6).…”