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

This article reviews recent evidence revealing previously unrecognized anatomical contacts between sensory neurons and various epidermal cells—including keratinocytes, Merkel cells, Langerhans cells, and melanocytes—that form a complex neuro-immuno-cutaneous network in human skin. It highlights that keratinocytes and Merkel cells act as active sensory transducers communicating with sensory neurons via chemical synapse-like contacts, challenging the traditional view that sensory neurons alone mediate touch, pain, temperature, and itch. Additionally, the review discusses how peptidergic intraepidermal free nerve endings (IEFN) release neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) to modulate immune responses via Langerhans cells and influence melanocyte proliferation and melanogenesis through synaptic-like contacts. These findings suggest that epidermal cells and sensory neurons engage in reciprocal communication essential for sensory perception and epidermal homeostasis, with implications for understanding inflammatory skin diseases and potential therapeutic targets.