Topically applied semaphorin 3A ointment inhibits scratching behavior and improves skin inflammation in NC/Nga mice with atopic dermatitis.

BACKGROUND: Epidermal hyperinnervation in atopic dermatitis (AD) is activated directly by various external stimuli, causing enhanced itching. Nerve density is regulated by the nerve repulsion factor semaphorin 3A (Sema3A), along with nerve elongation factors. OBJECTIVE: To investigate the effects of Sema3A ointment in the NC/Nga mouse model of AD. METHODS: An AD-like phenotype was induced by repeated application of Dermatophagoides farinae body (Dfb) ointment to the dorsal skin of NC/Nga mice. Vaseline, heparinoid, betamethasone, tacrolimus and recombinant Sema3A ointments were applied to the lesional skin once a day for 4 days. Transepidermal water loss (TEWL) was measured before and after each treatment. We also scored the degree of dermatitis and recorded videos to observe scratching behavior. Subsequently, we collected skin samples from these mice for histological analyses. RESULTS: Topical application of Sema3A, betamethasone and tacrolimus ointments significantly inhibited scratching behavior and improved dermatitis scores in Dfb-treated mice compared with control mice, whereas vaseline and heparinoid had no effects. A significant improvement of TEWL was observed only in Sema3A ointment-treated mice. Moreover, Sema3A ointment reduced the densities of PGP9.5- and substance P-immunoreactive nerve fibers in the epidermis and the numbers of inflammatory cells, such as CD4 immunoreactive T cells and eosinophils, and improved acanthosis in the Dfb-treated mice compared with controls. CONCLUSION: Sem3A ointment may have therapeutic efficacy in patients with pruritus and dermatitis of AD.

Visual analogue scale: evaluation of the instrument for the assessment of pruritus.

The aim of this study was to evaluate the visual analogue scale (VAS) as a method of pruritus assessment. A total of 310 subjects with pruritic dermatoses (148 Caucasian subjects and 162 Asian subjects) were recruited. The patients assessed pruritus intensity using the horizontal and vertical VAS, numeric rating scale (NRS) and verbal rating scale (VRS). All scales showed very good reproducibility (intraclass coefficient (ICC) > 0.8). No significant differences were found between the horizontal and vertical VAS (5.3 ± 2.9 vs. 5.3 ± 3.0 points, p = 0.34). Using NRS, patients rated their pruritus significantly higher than with VAS (5.7 ± 2.6 points, p < 0.01). VRS showed the highest correlation with NRS (R = 0.82, p < 0.001), followed by horizontal (R = 0.75, p < 0.001) and vertical VAS (R=0.74, p < 0.001). Based on detailed analysis following VAS categories were proposed: 0 = no pruritus, > 0-< 4 points = mild pruritus, ≥ 4-< 7 points = moderate pruritus, ≥ 7-< 9 points = severe pruritus, and ≥ 9 points = very severe pruritus. In conclusion, the VAS is a valuable method of pruritus measurement.

Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch.

BACKGROUND: Psoriasis is a complex, multifactorial inflammatory skin disease with genetic and environmental interactions. Patients with psoriasis exhibit erythematous plaques with itch, but the mechanisms of psoriatic itch are poorly understood. OBJECTIVES: This study was performed to investigate epidermal nerve density and opioid receptor levels in psoriatic skin with or without itch. METHODS: Twenty-four patients with psoriasis aged between 39 and 82 years were included in this study. The number of epidermal nerve fibres, the levels of semaphorin 3A (Sema3A) and the expression patterns of µ- and κ-opioid systems were examined immunohistologically in skin biopsies from psoriatic patients with or without itch and healthy volunteers as controls. RESULTS: The number of epidermal nerve fibres tended to increase in approximately 40% of psoriatic patients with itch compared with healthy controls, while such intraepidermal nerves were not observed in other itchy patients. In comparison with healthy controls, Sema3A levels also tended to decrease in the epidermis of psoriatic patients with itch. However, no relationship was found between nerve density and Sema3A levels in the epidermis of psoriatic patients with itch. The levels of µ-opioid receptor and ß-endorphin in the epidermis were the same in healthy controls and psoriatic patients with or without itch. The levels of κ-opioid receptor and dynorphin A were significantly decreased in the epidermis of psoriatic patients with itch compared with healthy controls. CONCLUSIONS: Based on Sema3A levels in the epidermis, epidermal opioid systems, rather than hyperinnervation, may be involved in the pathogenesis of psoriatic itch.

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.

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.