A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1 Ferda Cevikbas, PhD, Xidao Wang, PhD,

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A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1 Ferda Cevikbas, PhD, Xidao Wang, PhD, Tasuku Akiyama, PhD, Cordula Kempkes, PhD, Terhi Savinko, PhD, Attila Antal, MD, Gabriela Kukova, MD, Timo Buhl, MD, Akihiko Ikoma, MD, PhD, Joerg Buddenkotte, PhD, Vassili Soumelis, MD, Micha Feld, PhD, Harri Alenius, PhD, Stacey R. Dillon, PhD, Earl Carstens, PhD, Bernhard Homey, MD, Allan Basbaum, PhD, Martin Steinhoff, MD, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 2, Pages 448-460.e7 (February 2014) DOI: 10.1016/j.jaci.2013.10.048 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-31 derives from human TH2 cells, and IL-31RA is expressed on human DRG neurons. A, qPCR of IL-31, the IL-31RA long isoform, the IL-31RA short isoform, and OSMRβ. B, Colocalization of cutaneous lymphocyte–associated antigen (red) and IL-31 (green) in AD skin. Scale bar = 100 μm. C, Human TH2 cells express IL-31 mRNA. D, Mature (mDC) dendritic cells express IL-31 mRNA. EC, Endothelial cells; Fb, fibroblast; KC, keratinocyte. E, IL-31RA immunostaining in human DRG neurons. Scale bar = 50 μm. F, Control. ***P < .001, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Superantigen-induced upregulation of IL-31 in an AD-like mouse model. A, Treatment regimen. B, Hematoxylin and eosin staining of vehicle (PBS)– and SEB-treated skin. Scale bar = 200 μm. C and D, Number of CD3+ T cells (Fig 2, C) and eosinophils (Fig 2, D) in vehicle- versus SEB-treated skin. E and F, qPCR from skin samples reveals increased mRNA levels for IL-31 (Fig 2, E) and IL-4 (Fig 2, F) in SEB-treated skin. N = 8 mice per group. **P < .01 and ***P < .001, Student t test. Error bars indicate SEMs. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 In vivo effects of IL-31 in mice. A, Injection of IL-31 into the nape of neck induced profound scratching. B, Intraplantar IL-31 significantly increased paw licking. C and D, Cheek injection of IL-31 only produced scratching (Fig 3, C) but no wiping (Fig 3, D). E, Intrathecal injection of IL-31 induced significant dose-dependent scratching compared with vehicle. N = 8 mice per group. **P < .01 and ***P < .001, Student t test. Error bars indicate SEMs. n.s., Not significant. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Localization of IL-31RA in murine DRG and SC. A, IL-31RA+ (red) and TRPV1+ (green) neurons partly colocalize. B, Minimal overlap of IL-31RA (red) and IB4+ (green) subset of nonpeptidergic nociceptors. C, No overlap of IL-31RA+ (red) and N52+ unmyelinated neurons (green). D, IL-31RA+/TRPV1+ in nerve terminals of the superficial dorsal horn. Intrathecal capsaicin (i.t. cap.); (E) but not vehicle (Fig 4, D) ablated TRPV1+ (green) and IL-31RA (red) immunoreactivity. Scale bars = 100 μm. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Neuronal requirement of IL-31–induced itch. A, Depletion of TRPV1+ neurons by intrathecal capsaicin (i.t. cap) significantly decreased intrathecal IL-31–induced scratching. B and C, TRPV1 KO (Fig 5, B) and TRPA1 KO (Fig 5, C) mice show reduction in IL-31–induced scratching compared with WT littermates. D and E, c-kit mutant mice (Fig 5, D) and PAR-2 KO mice (Fig 5, E) showed equal scratching to WT mice after IL-31 injection. N = 8 mice per group. **P < .01 and ***P < .001, Student t-test. n.s., Not significant. Error bars indicate SEMs. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-31–induced calcium mobilization and characterization of IL-31–responsive DRG neurons. A, Neurons responding to IL-31 only (blue), histamine only (green), IL-31 and histamine (black), and neither IL-31 nor histamine (red). B, Percentages of IL-31–responsive neurons, which also respond to other compounds. C and D, Venn diagrams for DRG neurons in percentages. E, Percentages of IL-31–responsive neurons in different KO mice. N = 193 to 981 cells per group. For quantification, 10 to 30 dishes per group were used, and 20 to 50 cells per dish were counted. *P < .05, **P < .01, and ***P < .001, unpaired t test. Error bars indicate SEMs. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 ERK1/2 phosphorylation in DRG is critical for IL-31–induced itch. A and B, Western blotting (Fig 7, A) and densitometric analysis (Fig 7, B) of murine cultured DRG neurons for phospho-ERK (pERK) 1/2 illustrate peak activation of ERK1/2 after 5 minutes. C, Pretreatment with the ERK1/2 inhibitor U0126 blocked IL-31–induced ERK1/2 activation. D, IL-31 stimulation does not lead to p38 phosphorylation in cultured DRG neurons. E, Intraperitoneal injection of U0126 before IL-31 blocked IL-31–evoked scratching. N = 8 mice per group. **P < .01 and ***P < .001, Student t test. Error bars indicate SEMs. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 OVA-induced skin inflammation in mice. A, Topical treatment of mice during a maximum period of 51 days with OVA (100 μg in PBS) or vehicle was performed as indicated in the time scale diagram. B, Histologic features of hematoxylin and eosin–stained skin sites topically treated with either OVA or vehicle. Scale bar = 200 μm. C, Quantitative analysis for CD3+ cells after repeated topical exposure to OVA or vehicle reveals higher numbers of CD3+ cells in the OVA-treated compared with the vehicle-treated group. D, Eosinophil infiltration was significantly higher in OVA-treated skin compared with the vehicle (PBS) control group. E and F, qPCR analysis of IL-31 (Fig E1, E) and IL-4 (Fig E1, F) in skin biopsy specimens after OVA treatment reveals significantly increased expression for both TH2-related cytokines compared with the vehicle control. **P < .01 and ***P < .001, Student t test (SEM). Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Colocalization of IL-31RA with neuronal markers in murine TG tissue. A, All IL-31RA+ neurons (red) colocalized with TRPV1+ neurons (green). B, IL-31RA+ neurons (red) showed minimal overlap with IB4+ neurons (green). C, No colocalization of IL-31RA+ neurons (red) with N52 (green), a marker for myelinated neurons. Scale bar = 100 μm. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Specificity of the IL-31RA antibody was tested in DRG neurons of IL-31RA KO and WT mice. IL-31RA+ immunoreactivity was detected in DRG neurons of WT mice. No signal was detectable in IL-31RA KO DRG tissue. Scale bar = 100 μm. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Intradermal IL-31 activates murine dorsal horn nociresponsive neurons. All cells were isolated by using the IL-31 search strategy described in the Methods section. A, Mean peristimulus time histograms show, from left to right, unit responses to 2 successive intradermal IL-31 injections into the hind paw without testing the receptive field. Units that had a chemical receptive field were then classified by an electrode readjusted to identify firing units to IL-31. IL-31 injection was followed by single injections of SLIGRL-NH2, histamine, brush, pinch, AITC, capsaicin, noxious heat, cooling, or vehicle. Numbers in parentheses provide the number of responders in relation to the total number of neurons tested. The left inset shows histologically recovered recordings sites (circles) compiled on a representative section of the lumbar enlargement. Error bars (gray) indicate SEMs. B, Peristimulus time histogram (bin width: 1 s) shows a representative single dorsal horn neuron response to intradermal IL-31 (left peristimulus time histogram), followed by SLIGRL-NH2, histamine, graded mechanical, AITC, capsaicin, heat, cold and vehicles (saline, Tween-80, and mineral oil). This neuron responded to all stimuli but not the vehicles. The left inset shows the recording site (dot) in the lumbar superficial dorsal horn. C, Quantification. Thin lines plot each unit's spontaneous activity (SA; recorded for 3 minutes) and response to 2 successive intradermal microinjections of IL-31 (analyzed for 10 minutes) at 30-minute interval. The thick line shows the mean of 5 units tested. Error bars indicate SEMs. *Mean response (P < .05, paired t test) to the first injection of IL-31 is significantly different from SA. #Mean response (P < .05) to the second injection of IL-31 is significantly different from the first response. Journal of Allergy and Clinical Immunology 2014 133, 448-460.e7DOI: (10.1016/j.jaci.2013.10.048) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions