Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis

Background: Itch impairs the quality of life for many patients with dermatoses, especially atopic dermatitis (AD), and is frequently induced by a warm environment. Objective: To determine the mechanism underlying itch induction by warmth, we focused on artemin, a member of glial cell line-derived neurotrophic factors (GDNFs). Methods: A gene array assay revealed that artemin was expressed in substance P-treated dermal fibroblasts. The expression of artemin in healthy and AD-lesional skin was evaluated with immunohistochemistry and in situ hybridization. The impact of fibroblast-derived artemin on the proliferation and morphology of neural cell was investigated in vitro. To confirm the involvement of artemin in skin sensibility, wild-type and GDNF family receptor alpha 3 knockout mice were employed for sensory examination. Results: Artemin-expressing fibroblasts accumulated in skin lesions of patients with AD. Artemin induced cell proliferation of a neuroblastoma cell line in vitro, and intradermal injection of artemin in mice resulted in peripheral nerve sprouting and thermal hyperalgesia. Artemin-treated mice demonstrated scratching behavior in a warm environment, but mice deficient for GDNF family receptor alpha 3, a potent artemin receptor, did not show this behavior. Furthermore, the escaping response to heat stimulus was attenuated in GDNF family receptor alpha 3 knockout mice, suggesting that artemin may contribute to sensitivity to heat. Conclusion: These data suggest that dermal fibroblasts secrete artemin in response to substance P, leading to abnormal peripheral innvervation and thermal hyperalgesia. We hypothesize that artemin lowers the threshold of temperature-dependent itch sensation and might therefore be a novel therapeutic target for treating pruritic skin disorders, including AD. (J Allergy Clin Immunol 2012;130:671-82.)