Keratinocyte-derived anosmin-1, an extracellular glycoprotein encoded by the X-linked Kallmann syndrome gene, is involved in modulation of epidermal nerve density in atopic dermatitis

Tengara S, Tominaga M, Kamo A, Taneda K, Negi O, Ogawa H, Takamori K.
Source: J Dermatol Sci
Publication Date: (2010)
Issue: 58(1):: 64-71
Research Area:
Dermatology/Tissue Engineering
Basic Research
Cells used in publication:
Dorsal root gang. (DRG), rat
Species: rat
Tissue Origin: brain
Keratinocyte, (NHEK-Ad) human adult
Species: human
Tissue Origin: dermal
Keratinocyte, (NHEK-neo) human neonatal
Species: human
Tissue Origin: dermal
BACKGROUND: Epidermal nerve density is increased in atopic dermatitis (AD), suggesting that the hyperinnervation is partly responsible for abnormal itch perception. It is probably controlled by axonal guidance molecules produced by keratinocytes. An extracellular matrix glycoprotein anosmin-1 encoded by KAL1 has chemoattractive or chemorepulsive effects on different neuronal types. OBJECTIVE: This study was performed to investigate the roles of anosmin-1 in skin innervation. METHODS: Rat dorsal root ganglion (DRG) neurones were cultured in conditioned medium from control or KAL1-overexpressing cells for neurite outgrowth assay. KAL1 expression in cultured epidermal keratinocytes or human skin was examined by quantitative RT-PCR (qRT-PCR). Anosmin-1 distribution in normal and atopic skin was examined immunohistochemically. The effects of calcium concentrations and cytokines on KAL1 expression in cultured normal human epidermal keratinocytes (NHEK) were analysed by qRT-PCR. RESULTS: Neurite outgrowth in cultured DRG neurones was inhibited by conditioned medium from KAL1-overexpressing cells, while it was rescued by addition of recombinant fibroblast growth factor receptor 1 for capturing anosmin-1. KAL1 transcripts were expressed in cultured keratinocytes or in normal skin. Anosmin-1 was strongly expressed in the basal cell layer of normal skin, but decreased in atopic skin, concomitant with increases of epidermal nerve fibres. KAL1 expression was downregulated during keratinocyte differentiation. The expression was also upregulated by interleukin-4 (IL-4), IL-13 or transforming growth factor (TGF)-beta1. TGF-beta1 acted synergistically with IL-13 to enhance KAL1 expression, while interferon-gamma inhibited its expression. CONCLUSION: Anosmin-1 produced by epidermal keratinocytes in response to calcium concentrations or cytokines may modulate epidermal nerve density in AD.