CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.

Détails

Ressource 1Télécharger: 1-s2.0-S0022202X18318748-main.pdf (6224.84 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_3EF8D0F9BAD4
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
Périodique
The Journal of investigative dermatology
Auteur(s)
Mellett M., Meier B., Mohanan D., Schairer R., Cheng P., Satoh T.K., Kiefer B., Ospelt C., Nobbe S., Thome M., Contassot E., French L.E.
ISSN
1523-1747 (Electronic)
ISSN-L
0022-202X
Statut éditorial
Publié
Date de publication
09/2018
Peer-reviewed
Oui
Volume
138
Numéro
9
Pages
2010-2023
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule 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 T helper type 17 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 T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.
Mots-clé
Animals, CARD Signaling Adaptor Proteins/genetics, CARD Signaling Adaptor Proteins/metabolism, Cells, Cultured, Cytokines/metabolism, DNA/genetics, DNA Mutational Analysis, Disease Models, Animal, Female, Gain of Function Mutation, Guanylate Kinases/genetics, Guanylate Kinases/metabolism, Humans, Inflammation/genetics, Inflammation/metabolism, Inflammation/pathology, Interleukin-17/metabolism, Interleukin-23/metabolism, Keratinocytes/metabolism, Keratinocytes/pathology, Membrane Proteins, Mice, Psoriasis/genetics, Psoriasis/metabolism, Psoriasis/pathology
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/04/2018 16:48
Dernière modification de la notice
20/08/2019 13:35
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