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CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation
Mark Mellett1, Barbara Meier1, Deepa Mohanan1
1Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland.
Insights
Gain-of-function mutations in CARD14 cause psoriasis. Mice with a CARD14 mutation developed psoriatic skin, driven by the IL-23/IL-17 pathway, demonstrating CARD14
Area of Science:
- Dermatology
- Immunology
- Genetics
Background:
- Mutations in CARD14 are linked to psoriasis susceptibility.
- The in vivo impact of CARD14 gain-of-function mutations is not fully understood.
Purpose of the Study:
- To investigate the in vivo physiological impact of CARD14 gain-of-function mutations.
- To elucidate the role of CARD14 in psoriatic disease pathogenesis.
Main Methods:
- Generated heterozygous mice with a CARD14 gain-of-function mutation (Card14ΔE138).
- Analyzed skin phenotype, including lesions, epidermal changes, and immune cell infiltration.
- Assessed cytokine and chemokine expression, particularly related to the IL-23/IL-17 axis.
- Utilized IL-23p19 neutralization to assess its therapeutic effect.
Main Results:
- Mice with Card14ΔE138 mutation spontaneously developed chronic psoriatic skin lesions, epidermal thickening, and hyperkeratosis.
- Affected skin showed elevated antimicrobial peptides, chemokines, and T helper type 17 cell-signature cytokines.
- Immune infiltrates included neutrophils, myeloid cells, and T cells, mirroring human psoriasis.
- IL-23p19 neutralization significantly reduced skin lesions and inflammatory markers.
Conclusions:
- CARD14 hyperactivation is sufficient to drive T helper type 17-mediated psoriatic skin disease in vivo.
- The IL-23/IL-17 axis is a critical pathway in CARD14-driven psoriasis pathogenesis.
- CARD14 gain-of-function mutations orchestrate a complex immune response characteristic of psoriasis.
Abstract:
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.
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