CHARACTERIZATION OF UNMYELINATED AXONS UNITING EPIDERMAL AND DERMAL IMMUNE CELLS IN PRIMATE AND MURINE SKIN

The present study was undertaken to characterize further the structure and function of cutaneous nerves which we have previously shown to as sociate with skin immune cells (Hosoi et al., Nature 1993: 363:159). U ltrastructurally, axons were prominent within the superficial dermis a nd epidermis in neonatal murine skin, but they were inconspicuous in a dult murine and primate skin, Immunohistochemical and immunoultrastruc tural evaluation of normal adult human and simian skin for neural cell adhesion molecule (N-CAM), however, defined a plexus of axons surroun ding superficial dermal mast cells and extending as delicate, vertical branches into the overlying epidermal la) er. Antibodies to neuropept ides substance P, calcitonin gene-related peptide, and to nerve cell-s pecific clathrin (LCb subunit) also reacted with this neural plexus. D ouble labeling disclosed intimate associations of N-CAM-positive axons with dermal chymase-positive mast cells as well as with epidermal CD1 a-positive Langerhans' cells by confocal scanning laser microscopy. Fu nctionally, capsaicin applied to forearm skin revealed by 6 h discharg e of mast cell chymase and induction of E-selectin in adjacent microva scular endothelium, events consistent with release of substance P from axons and subsequent stimulation of cytokine-mediated mast cell-endot helial interaction. Identical application of capsaicin to human skin x enografted to immunodeficient mice, and thus experimentally lacking in unmyelinated axons, failed to show similar findings. These results pr ovide additional support to the concept that an elaborate network of c utaneous axons may play a functional role in regulation of skin inflam mation and immunity.