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Botulinum neurotoxin A decreases infiltrating cutaneous lymphocytes and improves acanthosis in the KC-Tie2 mouse model.

Ward NL, Kavlick KD, Diaconu D, Dawes SM, Michaels KA, Gilbert E - J. Invest. Dermatol. (2012)

View Article: PubMed Central - PubMed

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Psoriatic skin contains more nerve fibers, has increased levels of sensory nerve-derived calcitonin gene related peptide (CGRP) and substance P (SP), and psoriasis disease severity can be exacerbated by stress possibly by increasing cutaneous nerve numbers and SP and CGRP expression... Recent work by our group identified increases in cutaneous nerve fibers and nerve-derived SP and CGRP in the KC-Tie2 murine model of psoriasiform dermatitis, providing an experimental paradigm to explore neural contributions to psoriasis pathogenesis... Surgical elimination of the cutaneous nerves in KC-Tie2 mouse dorsal skin resulted in a 30% improvement in acanthosis, a 40% decrease in CD11c dendritic cells (DCs) and a 30% decrease in CD4 T cells... These outcomes were SP and CGRP dependent; as reconstitution of SP and CGRP in denervated KC-Tie2 skin prevented improvement in the phenotype and inhibition of SP and CGRP in innervated KC-Tie2 skin recapitulated the findings elicited by experimental denervation in a sensory neuropeptide specific manner... These findings provide insight into potential mechanisms underlying clinical reports of disease improvement following nervous system injury and identify key roles for nerve derived SP and CGRP in sustaining chronic psoriasiform skin inflammation... Adult KC-Tie2 mouse dorsal skin was intradermally injected with BoNT-A (Dysport®; 9units/kg/100ul) and saline (100ul volume) in anatomically separate locations, the regions were marked and images were taken to ensure that the same locations were harvested for analyses... All animal protocols were approved by the Case Western Reserve University institutional animal care and use committee... Dorsal skin injected once with BoNT-A showed significant improvement in acanthosis compared to saline injected skin at 2 weeks (~17% decrease; P=0.031) and at 6 weeks (~25% decrease; P=0.011; Figure 1a–b; Figure 2)... Dermal DC infiltration was also significantly reduced, evidenced by a significant decrease in the number of dermal CD11c DCs in BoNT-A injected skin compared to saline injected skin (Figure 1c–d; Figure 2) at 2 weeks (29% decrease; P=0.002) and at 6 weeks (38% decrease; P<0.0001)... CD4 T cell numbers also decreased significantly in BoNT-A injected skin compared to saline injected skin (Figure 1e–f; Figure 2) at 2 weeks (24% decrease; P=0.017) and at 6 weeks (34% decrease; P<0.002)... The number of F4/80 macrophages and CD8 T cells did not differ between BoNT-A and saline injected skin, nor were any changes observed for dermal angiogenesis (blood vessel number or size) at either of the time points examined (not shown)... These findings demonstrate a significant improvement in psoriasiform skin inflammation and epidermal hyperplasia following one intradermal injection of BoNT-A, and identify decreases in infiltrating CD4 T cells and CD11c DCs that occur concomitant with the improvement in acanthosis.

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Botulinum neurotoxin A (BoNT-A) improves skin disease severity in KC-Tie2 miceRepresentative images of H&E (a–b), CD11c (c–d) and CD4 (e–f) immunostained back skin of KC-Tie2 animals 6 weeks following a single intradermal injection of either saline (a, c, e) or BoNT-A (b, d, f; Dysport®, 9units/kg). Scale bar = 100 μM.
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Figure 1: Botulinum neurotoxin A (BoNT-A) improves skin disease severity in KC-Tie2 miceRepresentative images of H&E (a–b), CD11c (c–d) and CD4 (e–f) immunostained back skin of KC-Tie2 animals 6 weeks following a single intradermal injection of either saline (a, c, e) or BoNT-A (b, d, f; Dysport®, 9units/kg). Scale bar = 100 μM.

Mentions: Dorsal skin injected once with BoNT-A showed significant improvement in acanthosis compared to saline injected skin at 2 weeks (~17% decrease; P=0.031) and at 6 weeks (~25% decrease; P=0.011; Figure 1a–b; Figure 2). Dermal DC infiltration was also significantly reduced, evidenced by a significant decrease in the number of dermal CD11c+ DCs in BoNT-A injected skin compared to saline injected skin (Figure 1c–d; Figure 2) at 2 weeks (29% decrease; P=0.002) and at 6 weeks (38% decrease; P<0.0001). CD4+ T cell numbers also decreased significantly in BoNT-A injected skin compared to saline injected skin (Figure 1e–f; Figure 2) at 2 weeks (24% decrease; P=0.017) and at 6 weeks (34% decrease; P<0.002). The number of F4/80+ macrophages and CD8+ T cells did not differ between BoNT-A and saline injected skin, nor were any changes observed for dermal angiogenesis (blood vessel number or size) at either of the time points examined (not shown).


Botulinum neurotoxin A decreases infiltrating cutaneous lymphocytes and improves acanthosis in the KC-Tie2 mouse model.

Ward NL, Kavlick KD, Diaconu D, Dawes SM, Michaels KA, Gilbert E - J. Invest. Dermatol. (2012)

Botulinum neurotoxin A (BoNT-A) improves skin disease severity in KC-Tie2 miceRepresentative images of H&E (a–b), CD11c (c–d) and CD4 (e–f) immunostained back skin of KC-Tie2 animals 6 weeks following a single intradermal injection of either saline (a, c, e) or BoNT-A (b, d, f; Dysport®, 9units/kg). Scale bar = 100 μM.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375348&req=5

Figure 1: Botulinum neurotoxin A (BoNT-A) improves skin disease severity in KC-Tie2 miceRepresentative images of H&E (a–b), CD11c (c–d) and CD4 (e–f) immunostained back skin of KC-Tie2 animals 6 weeks following a single intradermal injection of either saline (a, c, e) or BoNT-A (b, d, f; Dysport®, 9units/kg). Scale bar = 100 μM.
Mentions: Dorsal skin injected once with BoNT-A showed significant improvement in acanthosis compared to saline injected skin at 2 weeks (~17% decrease; P=0.031) and at 6 weeks (~25% decrease; P=0.011; Figure 1a–b; Figure 2). Dermal DC infiltration was also significantly reduced, evidenced by a significant decrease in the number of dermal CD11c+ DCs in BoNT-A injected skin compared to saline injected skin (Figure 1c–d; Figure 2) at 2 weeks (29% decrease; P=0.002) and at 6 weeks (38% decrease; P<0.0001). CD4+ T cell numbers also decreased significantly in BoNT-A injected skin compared to saline injected skin (Figure 1e–f; Figure 2) at 2 weeks (24% decrease; P=0.017) and at 6 weeks (34% decrease; P<0.002). The number of F4/80+ macrophages and CD8+ T cells did not differ between BoNT-A and saline injected skin, nor were any changes observed for dermal angiogenesis (blood vessel number or size) at either of the time points examined (not shown).

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Psoriatic skin contains more nerve fibers, has increased levels of sensory nerve-derived calcitonin gene related peptide (CGRP) and substance P (SP), and psoriasis disease severity can be exacerbated by stress possibly by increasing cutaneous nerve numbers and SP and CGRP expression... Recent work by our group identified increases in cutaneous nerve fibers and nerve-derived SP and CGRP in the KC-Tie2 murine model of psoriasiform dermatitis, providing an experimental paradigm to explore neural contributions to psoriasis pathogenesis... Surgical elimination of the cutaneous nerves in KC-Tie2 mouse dorsal skin resulted in a 30% improvement in acanthosis, a 40% decrease in CD11c dendritic cells (DCs) and a 30% decrease in CD4 T cells... These outcomes were SP and CGRP dependent; as reconstitution of SP and CGRP in denervated KC-Tie2 skin prevented improvement in the phenotype and inhibition of SP and CGRP in innervated KC-Tie2 skin recapitulated the findings elicited by experimental denervation in a sensory neuropeptide specific manner... These findings provide insight into potential mechanisms underlying clinical reports of disease improvement following nervous system injury and identify key roles for nerve derived SP and CGRP in sustaining chronic psoriasiform skin inflammation... Adult KC-Tie2 mouse dorsal skin was intradermally injected with BoNT-A (Dysport®; 9units/kg/100ul) and saline (100ul volume) in anatomically separate locations, the regions were marked and images were taken to ensure that the same locations were harvested for analyses... All animal protocols were approved by the Case Western Reserve University institutional animal care and use committee... Dorsal skin injected once with BoNT-A showed significant improvement in acanthosis compared to saline injected skin at 2 weeks (~17% decrease; P=0.031) and at 6 weeks (~25% decrease; P=0.011; Figure 1a–b; Figure 2)... Dermal DC infiltration was also significantly reduced, evidenced by a significant decrease in the number of dermal CD11c DCs in BoNT-A injected skin compared to saline injected skin (Figure 1c–d; Figure 2) at 2 weeks (29% decrease; P=0.002) and at 6 weeks (38% decrease; P<0.0001)... CD4 T cell numbers also decreased significantly in BoNT-A injected skin compared to saline injected skin (Figure 1e–f; Figure 2) at 2 weeks (24% decrease; P=0.017) and at 6 weeks (34% decrease; P<0.002)... The number of F4/80 macrophages and CD8 T cells did not differ between BoNT-A and saline injected skin, nor were any changes observed for dermal angiogenesis (blood vessel number or size) at either of the time points examined (not shown)... These findings demonstrate a significant improvement in psoriasiform skin inflammation and epidermal hyperplasia following one intradermal injection of BoNT-A, and identify decreases in infiltrating CD4 T cells and CD11c DCs that occur concomitant with the improvement in acanthosis.

Show MeSH
Related in: MedlinePlus