Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis Hiroyuki Murota, MD, PhD, Mayuko Izumi, MSc,

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Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis Hiroyuki Murota, MD, PhD, Mayuko Izumi, MSc, Mostafa I.A. Abd El-Latif, MD, PhD, Megumi Nishioka, MD, Mika Terao, MD, PhD, Mamori Tani, MD, Saki Matsui, MD, Shigetoshi Sano, MD, PhD, Ichiro Katayama, MD, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 3, Pages 671-682.e4 (September 2012) DOI: 10.1016/j.jaci.2012.05.027 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 SP-treated fibroblasts express artemin. A, Result of macrogene array. Control: vehicle-treated. B, RT-PCR analysis of GDNF family, and NGF expression PDFs, NHDFs, and NHEKs. The data shown are representative of 2 independent experiments. C, Real-time PCR results in NHDF treated with various concentrations of SP for 6 hours. ∗P < .05. D, Sequential expression levels of artemin were examined by Western blot after treatment with 1 × 10−6 mol/L SP. ARTN, Artemin; GAPDH, glyceraldehyde-3-phosphate; NHEKs, normal human epidermal keratinocytes. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Accumulation of artemin in dermal fibroblasts from AD skin lesions. A, Healthy skin and an AD skin lesion (with disease duration of about 1 month) were stained for artemin. Dashed white lines represent the epidermal-dermal junction. AD skin lesion was costained for vimentin and artemin (B) or CD34 and artemin (C). Hoechst: Hoechst 33342. Dashed lines represent the vascular wall (Fig 2, C). D, In situ hybridization for artemin. Positive signal appeared with blue (indicated by arrows). The disease duration was 4 days for AD1 and about 1 month for AD2. The same skin sections were immunostained for SP. E, Lesional skin with disease duration of about 1 month was immunolabeled with PGP-9.5 and GFRα3. Arrows indicate costained nerve fibers. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 SH-SY5Y cells were cultured in conditioned medium derived from SP-treated NHDFs. A, RT-PCR analysis of the expression of GFRα family. B, Morphology of SH-SY5Y cells. Neurite outgrowth and neuronal morphology are indicated by arrows. C, The impact of artemin neutralization antibody on BrdU incorporation assay (n = 4). ∗P < .05, ∗∗P < .01. D, The impact of artemin neutralization antibody on the phosphorylation of RET in SH-SY5Y cells. DMEM, Dulbecco modified Eagle medium; GAPDH, glyceraldehyde-3-phosphate; NHEK, normal human epidermal keratinocyte; Phospho-RET, phosphorylated RET; RET, the receptor tyrosine kinase product of the c-ret proto-oncogene. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 The effect of artemin on skin innervation. A, Hindpaws of wild-type mice were intradermally injected with vehicle, artemin, or SP, and cutaneous peripheral nerve fibers were stained with PGP9.5 (green) and SP (red). Control indicates nontreated. B, The results in GFRα3KO mice. Scale bar: 100 μm. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Dysesthesia in GFRα3KO mice. A, Mechanosensation of wild-type (n = 5) and GFRα3KO (n = 5) mice. Force and latency indicated the actual force and latency time at the time of paw withdrawal reflex, respectively. Response to infrared heat stimulus (latency and thermal intensity to paw withdrawal) was measured with (B) Hargreaves test and (C) tail-flick test. Gray and black bars show results for wild-type (n = 5) and GFRα3KO mice (n = 5), respectively. D, The effect of exogenously administered artemin on Hargreaves test (n = 5). E, The effect of exogenously administered SP on Hargreaves test results was evaluated over time (n = 5, *P < .05 [0.5 vs 4 hours]). F, The effect of artemin-neutralization antibody on SP-induced thermal hyperalgesia. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Artemin-injected mice showed abnormal behavior in warm conditions. A, Artemin-injected wild-type mice were videotaped, and the time spent wiping their cheek was measured. Representative of 2 independent studies (n = 3 in each experiment). B, Artemin-injected GFRα3KO mice were videotaped, and the time spent wiping their cheek was measured. Representative of 2 independent studies (n = 3 in each experiment). C, The impact of capsazepine (CPZ) on artemin-induced abnormal behavior was measured (n = 3). ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Immunohistochemical staining for artemin (green) was performed with healthy skin and 2 AD skin lesions (disease duration of case 1 and case 2 was about 1 week and 3 months, respectively), nummular eczema skin lesions (disease duration of case 1 and case 2 was about 1 month and 2 months, respectively), prurigo nodularis skin lesions (disease duration of case 1 and case 2 was about 1 year and about 6 months, respectively), and psoriasis skin lesions (disease duration of case 1 and case 2 was about 1 week and about 1 month, respectively). Blue: Hoechst 33342. Dashed white lines represent the epidermal-dermal junction. Scale bar: 100 μm. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 To compare the number of dermal fibroblasts, healthy skin and 2 AD skin lesions (AD1 and AD2), which were identical to the sample in ISH analysis (Fig 2, D), were costained for vimentin. Results of hematoxylin and eosin (HE) staining and ISH for artemin (purple indicates a positive signal) are shown alongside vimentin-stained images (green: vimentin, blue: Hoechst 33342). Dashed white lines in the vimentin-stained images represent the epidermal-dermal junction. ISH, In situ hybridization. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Skin innervation in AD lesional skin was examined by immunolabeling for PGP-9.5 and artemin. PGP-9.5–positive peripheral nerve fibers (red) showed massive sprouting in the area with artemin accumulation (green) (magnification ×400). Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Artemin neutralization inhibited the rARTN-induced proliferation of SH-SY5Y cells, whereas an isotype matched control antibody did not. ARTN, Artemin; AARTNAb, artemin neutralizing antibody. *P < .05. Journal of Allergy and Clinical Immunology 2012 130, 671-682.e4DOI: (10.1016/j.jaci.2012.05.027) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions