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CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo


Mellett, Mark; Meier, Barbara; Mohanan, Deepa; Schairer, Rebekka; Cheng, Phil; Satoh, Takashi K; Kiefer, Betina; Ospelt, Caroline; Nobbe, Stephan; Thome, Margot; Contassot, Emmanuel; French, Lars E (2018). CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo. Journal of Investigative Dermatology, 138(9):2010-2023.

Abstract

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule, Caspase Recruitment Domain-Containing Protein 14 (CARD14), have been associated with an increased susceptibility to psoriasis but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines and cytokines (including Th17 cell-signature cytokines), and an immune infiltrate rich in neutrophils, myeloid cells and T-cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis and neutralization of IL-23p19, the key cytokine in maintaining Th17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and pro-inflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives Th17-mediated psoriasis skin disease in vivo.

Abstract

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule, Caspase Recruitment Domain-Containing Protein 14 (CARD14), have been associated with an increased susceptibility to psoriasis but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines and cytokines (including Th17 cell-signature cytokines), and an immune infiltrate rich in neutrophils, myeloid cells and T-cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis and neutralization of IL-23p19, the key cytokine in maintaining Th17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and pro-inflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives Th17-mediated psoriasis skin disease in vivo.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Cell Biology, Biochemistry, Molecular Biology, Dermatology
Date:21 April 2018
Deposited On:24 May 2018 09:00
Last Modified:30 Nov 2018 10:50
Publisher:Elsevier
ISSN:0022-202X
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jid.2018.03.1525
PubMed ID:29689250

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