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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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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.
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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.

Mentions: The most striking observation was a 50% decrease in the number of dermal CD11c+ cells in denervated skin, representing a return to levels comparable to innervated littermate (non-KC-Tie2) controls (Figure 4a–d). DCs are potent producers of IL-23, and ELISA analyses revealed a 33% decrease in IL-23 protein expression in whole skin lysates isolated from denervated KC-Tie2 mouse back skin compared to sham operated innervated skin (Figure 4e).


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

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.
Mentions: The most striking observation was a 50% decrease in the number of dermal CD11c+ cells in denervated skin, representing a return to levels comparable to innervated littermate (non-KC-Tie2) controls (Figure 4a–d). DCs are potent producers of IL-23, and ELISA analyses revealed a 33% decrease in IL-23 protein expression in whole skin lysates isolated from denervated KC-Tie2 mouse back skin compared to sham operated innervated skin (Figure 4e).

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