Abstract
Although the possible involvement of neurotrophic factors in itchy skins of atopic dermatitis has been predicted, the exact mechanism by which itch is induced remains unclear. Since nerve growth factor (NGF) has crucial effects on development and functions of sensory nerves, we analyzed a correlation between NGF production at the affected site and scratching behavior in atopic NC/Nga mice. NC/Nga mice spontaneously develop atopic dermatitis-like skin lesions when they are raised in air-unregulated conventional circumstances. We quantified scratching behavior of NC/Nga mice with a novel scratch analyzer (SCLABA®; NOVELTEC INC., Kobe, Japan) during the development of atopic dermatitis and compared to clinical skin severity scores. We found that there was a strong correlation between the severity of dermatitis and the increase in the number of scratches, indicating that scratching behavior may exacerbate clinical skin conditions. NGF contents in the skin lesion of conventional NC/Nga mice were significantly higher than those of SPF NC/Nga mice. Positive reaction for NGF was observed in keratinocytes and fibroblasts in affected skins of conventional NC/Nga mice. Immunohistochemical analysis showed the extension of PGP 9.5 positive nerve fibers from dermis toward epidermis at the affected skins. The protease-activated receptor (PAR) 2 has been reported to be expressed on peripheral nerve fibers and mediate neuronal activation. Thus, we attempted to produce a model with neurogenic itch by PAR2 stimulation. Seven days after intra-dermal injection of NGF, we injected a PAR2 agonist into the same sites of SPF NC/Nga mice. Scratching behavior was significantly increased in mice injected with NGF, but not in mice injected with diluent alone. These results suggest that sensory nerves induced by NGF may contribute to the appearance of itch through PAR2 activation. NGF produced at the affected skin may induce excessive extension of sensory nerves, resulting in abnormal skin sensitivity in atopic dermatitis.
