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Keratinocytes communicate with sensory neurons via synaptic-like contacts

Talagas, M;Lebonvallet, N;Leschiera, R;Sinquin, G;Elies, P;Haftek, M;Pennec, JP;Ressnikoff, D;La Padula, V;Garrec, RL;L'herondelle, K;Mignen, O;Le Pottier, L;Kerfant, N;Reux, A;Marcorelles, P;Misery, L;

Pain, temperature and itch are conventionally thought to be exclusively transduced by the intraepidermal nerve endings. While recent studies have shown that epidermal keratinocytes also participate in sensory transduction, the mechanism underlying keratinocyte communication with intraepidermal nerve endings remains poorly understood. We sought to demonstrate the synaptic character of the contacts between keratinocytes and sensory neurons and their involvement in sensory communication between keratinocytes and sensory neurons. Contacts were explored by morphological, molecular and functional approaches in cocultures of epidermal keratinocytes and sensory neurons. To interrogate whether structures observed in vitro were also present in the human epidermis, in situ correlative light electron microscopy was performed on human skin biopsies. Epidermal keratinocytes dialogue with sensory neurons through en passant synaptic-like contacts. These contacts have the ultrastructural features and molecular hallmarks of chemical synaptic-like contacts: narrow intercellular cleft, keratinocyte synaptic vesicles expressing synaptophysin and synaptotagmin 1, sensory information transmitted from keratinocytes to sensory neurons through SNARE-mediated, syntaxin1, vesicle release. By providing selective communication between keratinocytes and sensory neurons, synaptic-like contacts are the hubs of a two-site receptor. The permanent epidermal turnover, implying a specific en passant structure and a high plasticity, may have delayed their identification, thereby contributing to the long-held concept of nerve endings passing freely between keratinocytes. The discovery of keratinocyte-sensory neuron synaptic-like contacts may call for a reassessment of basic assumptions in cutaneous sensory perception and sheds new light on the pathophysiology of pain and itch as well as the physiology of touch. This article is protected by