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. 2011 Jul;131(7):1530-8.
doi: 10.1038/jid.2011.60. Epub 2011 Apr 7.

Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner

Stephen M Ostrowski  1 , Abdelmadjid Belkadi, Candace M Loyd, Doina Diaconu, Nicole L Ward
Affiliations

Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner

Stephen M Ostrowski et al. J Invest Dermatol. 2011 Jul.

Abstract

Nervous system involvement in psoriasis pathogenesis is supported by increases in nerve fiber numbers and neuropeptides in psoriatic skin and by reports detailing spontaneous plaque remission following nerve injury. Using the KC-Tie2 psoriasiform mouse model, we investigated the mechanisms by which nerve injury leads to inflammatory skin disease remission. Cutaneous nerves innervating dorsal skin of KC-Tie2 animals were surgically axotomized and beginning 1 day after denervation, CD11c(+) cell numbers decreased by 40% followed by a 30% improvement in acanthosis at 7 days and a 30% decrease in CD4(+) T-cell numbers by 10 days. Restoration of substance P (SP) signaling in denervated KC-Tie2 skin prevented decreases in CD11c(+) and CD4(+) cells, but had no effect on acanthosis; restoration of calcitonin gene-related peptide (CGRP) signaling reversed the improvement in acanthosis and prevented denervated-mediated decreases in CD4(+) cells. Under innervated conditions, small-molecule inhibition of SP in KC-Tie2 animals resulted in similar decreases to those observed following surgical denervation for cutaneous CD11c(+) and CD4(+) cell numbers; whereas small-molecule inhibition of CGRP resulted in significant reductions in CD4(+) cell numbers and acanthosis. These data demonstrate that sensory nerve-derived peptides mediate psoriasiform dendritic cell and T-cell infiltration and acanthosis and introduce targeting nerve-immunocyte/KC interactions as potential psoriasis therapeutic treatment strategies.

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Conflict of interest statement

Conflict of Interest

The authors state no conflict of interest.

Figures

Figure 1
Figure 1. KC-Tie2 mice have increased expression of neuropeptides in skin and DRG than control mice
Real time PCR was performed using primers targeting the neuropeptides somatostatin (SST), SP (SP), calcitonin gene related peptide (CGRP), vasoactive intestinal protein (VIP) and neuropeptide Y (NPY). (a) KC-Tie2 animals (n=4) have increased levels of SP and NPY expression in whole back skin as compared to control animals (n=4) and (b) increased level of SP and CGRP expression in their dorsal root ganglia (DRGs) as compared to control animals. p values are as indicated.
Figure 2
Figure 2. Surgical denervation of KC-Tie2 mouse skin results in decreased acanthosis
Representative images of H&E staining of sections of (a) control, (b) KC-Tie2 sham operated and (c) KC-Tie2 denervated back skin. (d) Epidermal thickness (in µM) of the sham operated side and the denervated side of back skin is presented for individual animals (n=13). The hatched line represents average epidermal thickness levels in innervated control mouse back skin. Representative images of Ki67 stained sections of (e) KC-Tie2 sham operated and (f) KC-Tie2 denervated back skin. p values are as indicated. Scale bar = 50µM.
Figure 3
Figure 3. CD4+ T cell numbers decrease in denervated skin while T cell derived cytokines remain unchanged
(a–c) Representative images of CD4 immunohistochemical staining in back skin sections of (a) control, (b) KC-Tie2 sham operated and (c) KC-Tie2 denervated back skin. (d) CD4+ T cell numbers in sham operated skin and denervated skin are presented for individual animals and are significantly decreased in KC-Tie2 denervated mouse skin compared to sham operated skin (n=10). The hatched line represents average number of CD4+ T cells in back skin of control mice. Western blotting (e) and ELISA (f–g) demonstrate no changes in IFNγ, IL-17 and IL-6 between sham operated and denervated KC-Tie2 mouse skin. p values are as indicated. Scale bar = 50µM.
Figure 4
Figure 4. Surgical denervation of KC-Tie2 mouse skin reduces CD11c+ dendritic cell numbers back to control mouse levels and decreases IL-23 protein expression
(a–c) Representative images of CD11c+ immunohistochemical staining in back skin sections of (a) control, (b) KC-Tie2 sham operated and (c) KC-Tie2 denervated back skin. (d) CD11c+ cell numbers in sham operated skin and denervated skin are presented for individual animals (n=11). The hatched line represents average number of CD11c+ cells in back skin of control mice. (e) ELISA analysis of IL-23 protein expression demonstrates a significant decrease in denervated skin compared to sham operated skin in KC-Tie2 mice. p values are as indicated. p values are as indicated. Scale bar = 50µM.
Figure 5
Figure 5. Restoration of neuropeptide signaling under denervated conditions returns CD11c+ and CD4+ cell numbers and acanthosis back to innervated conditions in a neuropeptide specific manner
Epidermal thickness (a), CD4+ cell number (b), and CD11c+ numbers (c) are presented for cohorts of animals (n=4 per group) that had PBS, SP receptor agonist (GR73632), or CGRP peptide injected intradermally into the denervated side of the back skin daily beginning one day after surgery. p values are as indicated.
Figure 6
Figure 6. Inhibition of SP or CGRP activity under innervated conditions mimics denervated-mediated changes to acanthosis and CD11c+ and CD4+ cell numbers in a neuropeptide specific manner
Epidermal thickness (a), CD4+ cell number (b), and CD11c+ T cell number data (c) are presented for cohorts of animals (n=4–6 per group) prior to (pre-treatment) and after (post-treatment) 30 days of treatment with either PBS, the selective SP receptor NK-1R antagonist (RP67580), or the CGRP antagonist, CGRP8–37. p values are as indicated.
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References

    1. Arck PC, Handjiski B, Peters EM, Peter AS, Hagen E, Fischer A, et al. Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways. Am J Pathol. 2003;162:803–814. - PMC - PubMed
    1. Arck PC, Slominski A, Theoharides TC, Peters EM, Paus R. Neuroimmunology of stress: skin takes center stage. J Invest Dermatol. 2006;126:1697–1704. - PMC - PubMed
    1. Casasco A, Marchetti C, Calligaro A, Casasco M, Poggi P, Beolchini M. Immunocytochemical labelling of Merkel cells of human oral mucosa by means of antibodies to protein gene product 9.5. Bull Group Int Rech Sci Stomatol Odontol. 1990;33:61–64. - PubMed
    1. Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, et al. Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A. 2005;102:2075–2080. - PMC - PubMed
    1. Chiang HY, Huang IT, Chen WP, Chien HF, Shun CT, Chang YC, et al. Regional difference in epidermal thinning after skin denervation. Exp Neurol. 1998;154:137–145. - PubMed

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