| First Author | Mellett M | Year | 2018 |
| Journal | J Invest Dermatol | PubMed ID | 29689250 |
| Mgi Jnum | J:262723 | Mgi Id | MGI:6164090 |
| Doi | 10.1016/j.jid.2018.03.1525 | Citation | Mellett M, et al. (2018) CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo. J Invest Dermatol |
| abstractText | 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 (Card14DeltaE138) 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. |
