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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:130

Article

Murota, Hiroyuki¹  Izumi, Mayuko¹  Abd El-Latif, Mostafa I. A.^1,2  Nishioka, Megumi¹  Terao, Mika¹  Tani, Mamori¹  Matsui, Saki¹  Sano, Shigetoshi³  Katayama, Ichiro¹ 

[1] Osaka Univ, Grad Sch Med, Dept Dermatol, Course Integrated Med, Suita, Osaka 5650871, Japan

[2] Cairo Univ, Dept Dermatol, Cairo, Egypt

[3] Kochi Univ, Dept Dermatol, Kochi, Japan

关键词: Artemin;    fibroblast;    substance P;    atopic dermatitis;    itch;    nerve fiber;    warmth;   

DOI  :  10.1016/j.jaci.2012.05.027

来源: Elsevier

【 摘 要 】

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.)

【 授权许可】

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