Anatomical contacts between sensory neurons and epidermal cells: an unrecognized anatomical network for neuro-immuno-cutaneous crosstalk

Sensory neurons innervating the skin are conventionally thought to be the sole transducers of touch, temperature, pain and itch. However, recent studies have shown that keratinocytes - like Merkel cells - act as sensory transducers, whether for innocuous or noxious mechanical, thermal or chemical stimuli, and communicate with intraepidermal free nerve endings via chemical synaptic contacts. This paradigm shift leads to consideration of the whole epidermis as a sensory epithelium. Sensory neurons additionally function as an efferent system. Through the release of neuropeptides in intimate neuroepidermal contact areas, they contribute to epidermal homeostasis and to the pathogenesis of inflammatory skin diseases. To counteract the dogma regarding neurocutaneous interactions, seen exclusively from the perspective of soluble and spreading mediators, this review highlights the essential contribution of the unrecognized anatomical contacts between sensory neurons and epidermal cells (keratinocytes, melanocytes, Langerhans cells and Merkel cells), which take part in the reciprocal dialogue between the skin, nervous system and immune system.