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

Ostrowski SM, Belkadi A, Loyd CM, Diaconu D, Ward NL - J. Invest. Dermatol. (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.

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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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 mannerEpidermal 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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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 mannerEpidermal 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.

Mentions: To confirm key functions for SP and CGRP in maintaining the psoriasiform skin phenotype in KC-Tie2 animals, we examined acanthosis and immune cell infiltration following treatment with either RP67580, a well characterized SP receptor antagonist (Arck et al., 2003) or with CGRP8–37, a well characterized selective CGRP receptor antagonist (Costa et al., 2008; Legat et al., 2004). Innervated KC-Tie2 mice were treated with RP67580 every other day or with CGRP8–37 or PBS daily for a period of 30d, a timepoint we previously showed was sufficient to reverse acanthosis and inflammation (Ward et al., 2010b; Wolfram et al., 2009). Examination of the skin revealed no changes in epidermal thickness or Ki67 immunostaining after treatment with PBS or RP67580 but a significant improvement in acanthosis and decreases in Ki67 staining in mice treated with CGRP8–37, reminiscent of what was observed following cutaneous surgical denervation (p=0.009; Figure 6a; Figure S4g–i). Examination of CD4+ cell numbers revealed significant decreases in dermal T cell numbers in KC-Tie2 mice that were treated with either RP67580 (p=0.03) or CGRP8–37 (p=0.01) but not PBS (Figure 6b). Finally, significant reductions in the CD11c+ cell population were only observed following treatment with the SP receptor antagonist (RP67580; p=0.001) and not PBS or CGRP8–37 (Figure 6c).


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

Ostrowski SM, Belkadi A, Loyd CM, Diaconu D, Ward NL - J. Invest. Dermatol. (2011)

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 mannerEpidermal 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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3116081&req=5

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 mannerEpidermal 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.
Mentions: To confirm key functions for SP and CGRP in maintaining the psoriasiform skin phenotype in KC-Tie2 animals, we examined acanthosis and immune cell infiltration following treatment with either RP67580, a well characterized SP receptor antagonist (Arck et al., 2003) or with CGRP8–37, a well characterized selective CGRP receptor antagonist (Costa et al., 2008; Legat et al., 2004). Innervated KC-Tie2 mice were treated with RP67580 every other day or with CGRP8–37 or PBS daily for a period of 30d, a timepoint we previously showed was sufficient to reverse acanthosis and inflammation (Ward et al., 2010b; Wolfram et al., 2009). Examination of the skin revealed no changes in epidermal thickness or Ki67 immunostaining after treatment with PBS or RP67580 but a significant improvement in acanthosis and decreases in Ki67 staining in mice treated with CGRP8–37, reminiscent of what was observed following cutaneous surgical denervation (p=0.009; Figure 6a; Figure S4g–i). Examination of CD4+ cell numbers revealed significant decreases in dermal T cell numbers in KC-Tie2 mice that were treated with either RP67580 (p=0.03) or CGRP8–37 (p=0.01) but not PBS (Figure 6b). Finally, significant reductions in the CD11c+ cell population were only observed following treatment with the SP receptor antagonist (RP67580; p=0.001) and not PBS or CGRP8–37 (Figure 6c).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.

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.

Show MeSH
Related in: MedlinePlus