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. 2017 Nov;158(11):2196-2202.
doi: 10.1097/j.pain.0000000000001025.

Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis

Kent Sakai  1 , Kristen M Sanders, Marina R Youssef, Kevin M Yanushefski, Liselotte E Jensen, Gil Yosipovitch, Tasuku Akiyama
Affiliations

Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis

Kent Sakai et al. Pain. 2017 Nov.

Abstract

Psoriasis is often accompanied by itch, but the mechanisms behind this symptom remain elusive. Dynamic changes in epidermal innervation have been observed under chronic itch conditions. Therefore, we investigated whether epidermal innervation is altered in the imiquimod-induced psoriasis mouse model, whether blockade of neurotrophic growth factor signaling can reduce these changes, and whether this system can impact psoriatic itch. Over the 7-day time course of imiquimod treatment, the density of epidermal nonpeptidergic nerves significantly increased, whereas the density of peptidergic nerves significantly decreased. The nonpeptidergic epidermal nerves expressed glial cell line-derived neurotrophic factor (GDNF) family receptor GFRα-1 and GFRα-2, the ligand-binding domains for GDNF and neurturin (NRTN). The NRTN mRNA expression was elevated in the skin of imiquimod-treated mice, whereas the GDNF mRNA expression was decreased. Treatment of imiquimod-challenged mice with an NRTN-neutralizing antibody significantly reduced nonpeptidergic nerve density as well as spontaneous scratching. These results indicate that NRTN contributes to an increase in the epidermal density of nonpeptidergic nerves in the imiquimod-induced psoriasis model, and this increase may be a factor in chronic itch for these mice. Therefore, inhibition of NRTN could be a potential treatment for chronic itch in psoriasis.

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Conflict of interest statement

Conflict of Interest

Y.G. has served as a consultant for Pfizer.

Figures

Fig. 1
Fig. 1. Increase in nonpeptidergic epidermal nerve fiber density in psoriasis model
(A–I) Skin was dissected from mice left untreated (Day 0, A,C,D,F,G,I) or after 2 (C,F,I) or 7 (B,C,E,F,H,I) days of imiquimod treatment. (A,B) Skin sections were immunostained with an antibody for β-tubulin to visualize all nerve fibers. (C) Total ENFD (epidermal nerve fiber density) was quantified at Day 0 (open bars), Day 2 (grey bars), and Day 7 (black bars). Error bars are S.E.M. (D,E). Skin sections were immunostained with antibodies for CGRP, a marker for peptidergic nerves. (F) As in C for peptidergic fibers immunostained with a CGRP antibody. * p< 0.05, significant difference from Day 0 (one-way ANOVA followed by Bonferroni post-test, F(2,9)=105.766, n = 4/group). (G,H) Skin sections were immunostained with antibodies for P2X3, a marker for nonpeptidergic nerves. The scale bar indicates 50 μm. (I) As in C for nonpeptidergic fibers immunostained with a P2X3 antibody. * p< 0.05, significant difference from Day 0 (one-way ANOVA followed by Bonferroni post-test, F(2,9)=7.303, n = 4/group).
Fig. 2
Fig. 2. Coexpression of P2X3 with GFRa-1 and GFRa-2 in psoriasis model
Skin sections from imiquimod-treated mice were immunostained with antibodies for P2X3 (red; A,D) and either GFRa-1 (green; B) or GFRa-2 (green; E) antibody. Merged images (C,F). The scale bar indicates 30 μm.
Fig. 3
Fig. 3. Increase of NRTN in imiquimod treated skin
(A) GDNF mRNA was measured in the skin of imiquimod-treated mice at Day 0 (white bars), Day 1 (grey bars), and Day 6 (black bars). Error bars are S.E.M. * p< 0.05, significant difference from Day 0 group (one-way ANOVA followed by Bonferroni post-test, F(2,11)=6.52, n = 4–5/group). (B) As in A, for NRTN. * p< 0.05, significant difference from Day 0 group (one-way ANOVA followed by Bonferroni post-test, F(2,15)=7.726, n = 6/group). (C–F) Typical examples of NRTN (green) and DAPI (blue) staining in the skin treated with imiquimod on Day 0 (C), Day 2 (D), and Day 7 (E). NRTN detection on Day 2 was blocked by preabsorption of the primary antibody with NRTN (F). The scale bar indicates 50 μm.
Fig. 4
Fig. 4. Reduction of spontaneous scratching and nonpeptidergic nerve fiber density by NRTN neutralizing antibody
Goat IgG control antibody (white bars), low-dose NRTN neutralizing antibody (LD, 0.04 μg/50 μL, gray bars) or high-dose NRTN neutralizing antibody (HD, 0.4 μg/50 μL, black bars) was intradermally injected into the imiquimod-treated area before each topical application of Aldara cream. (A) On Day 2 (left) or Day 7 (right), the skin was dissected and immunostained with a P2X3 antibody. ENFD (epidermal nerve fiber density) was counted. For comparison, dotted and dashed lines indicate data for Day 0 mice and mice treated with only Aldara cream, respectively (data from Fig. 1). Error bars are S.E.M. * p< 0.05, significant difference from IgG control-treated group (unpaired t-test or one-way ANOVA followed by Bonferroni post-test, F(2,11)=15.436, n = 4–6/group). (B) As in A for CGRP antibody. (C) Spontaneous scratching behavior was observed on Days 0, 2, and 7. Dashed lines indicate data for mice treated only with Aldara cream. Error bars are S.E.M. * p< 0.05, significant difference from IgG control-treated group (one-way ANOVA followed by Bonferroni post-test, F(2,15)=3.99, n = 5–7/group).
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