Characterization of unmyelinated axons uniting epidermal and dermal immune cells in primate and murine skin

Abstract

The present study was undertaken to characterize further the structure and function of cutaneous nerves which we have previously shown to associate with skin immune cells (Hosoi et al., Nature 1993: 363:159). Ultrastructurally, axons were prominent within the superficial dermis and epidermis in neonatal murine skin, but they were inconspicuous in adult murine and primate skin. Immunohistochemical and immunoultrastuctural evaluation of normal adult human and simian skin for neural cell adhesion molecule (N-CAM), however, defined a plexus of axons surrounding superficial dermal mast cells and extending as delicate, vertical branches into the overlying epidermal layer. Antibodies to neuropeptides substance P, calcitonin gene-related peptide, and to nerve cell-specific clathrin (LCb subunit) also reacted with this neural plexus. Double labeling disclosed intimate associations of N-CAM-positive axons with dermal chymase-positive mast cells as well as with epidermal CD1a-positive Langerhans' cells by confocal scanning laser microscopy. Functionally, capsaicin applied to forearm skin revealed by 6 h discharge of mast cell chymase and induction of E-selectin in adjacent microvascular endothelium, events consistent with release of substance P from axons and subsequent stimulation of cytokine-mediated mast cell-endothelial interaction. Identical application of capsaicin to human skin xenografted to immunodeficient mice, and thus experimentally lacking in unmyelinated axons, failed to show similar findings. These results provide additional support to the concept that an elaborate network of cutaneous axons may play a functional role in regulation of skin inflammation and immunity.

Scrapie Protein Degradation by Cysteine Proteases in CD11c + Dendritic Cells and GT1-1 Neuronal Cells

“…Prion spread to the peripheral nervous system may be facilitated by the fact that CD11c ϩ DC are in close contact with peripheral nerve fibers in the epithelium (17,22), which is in contrast to follicular DC, which are of a different origin and have different functions than the CD11c ϩ DC (12). In fact, in his original study, Langerhans described connections of the new type of cells in dermal epithelium (the DC that were later given his name) to nerve fibers, and he believed that the cells were of neuronal origin (27).…”

Mast Cells and Oral Inflammation

“…The same nerves that come into contact with LC were shown to form close associations with mast cells (MC CT ) (Walsh and Murphy, 1992b;Murphy, 1993;Egan et al, 1998;Pujic et al, 1998), and this raises the intriguing issue of the function of the LC/mast-cell connection, in the context of immune surveillance.…”

“…The genesis of the NIN concept was mapping studies that used multiple labeling to determine the spatial interactions between mucosal and cutaneous nerves and cells of the immune system. Close approximations of vertically ascending, unmyelinated nerve fibers with mast cells and Langerhans cells (LC) were demonstrated, initially in human skin (Walsh and Murphy, 1992b;Murphy, 1993;Hosoi et al, 1993;Walsh et al, 1996;Pujic et al, 1998) and subsequently in primate and murine skin (Egan et al, 1998) and human oral mucosa (Bartold et al, 2000). Of note, these nerves did not come into contact with stem cells, Merkel cells, or melanocytes, but rather were confined to the LC, immune surveillance cells that form a complex three-dimensional network by means of their extensive dendrites that traverse intercellular spaces between keratinocytes.…”

“…The preferred method in the author's laboratory is a sensitive double-or triple-labeling immunohistochemical technique that allows for the co-localization of two or three antigens in frozen tissue sections (Zhao et al, 1997;Pujic et al, 1998), since this is believed to result in an accurate assessment of mast-cell/nerve interactions. Useful markers to reveal the delicate neural plexus include neurofilaments, neural cell adhesion molecule, neuropeptides, and nerve-cell-specific clathrin (reviewed in Egan et al, 1998).…”

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

“…These trigger vasodilation, plasma protein extravasation, tissue edema, hemoconcentration, and leukocyte diapedesis [3]. C-fibers also modulate immune responses, with mast cells in close physical and chemical contact [4]. In turn, C-fiber signaling is modified by inflammatory signals, including serotonin, histamine, glutamate, adenosine triphosphate, adenosine, substance P, calcitonin-gene related peptide, bradykinin, eicosanoids prostaglandins, thromboxanes, leukotrienes, endocannabinoids, nerve growth factor, inflammatory cytokines, and protons.…”