Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland.
Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland.
J Invest Dermatol. 2018 Sep;138(9):2010-2023. doi: 10.1016/j.jid.2018.03.1525. Epub 2018 Apr 22.
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.
编码角质形成细胞信号分子 CARD14 的基因中罕见的常染色体显性突变与银屑病易感性增加有关，但 CARD14 功能获得性突变的生理影响在体内仍有待完全确定。在这里，我们报告说，携带 CARD14 功能获得性突变（Card14ΔE138）的杂合子小鼠自发地发展出一种慢性银屑病表型，具有特征性的鳞屑性皮肤损伤、表皮增厚、角质形成细胞过度增殖、角化过度和免疫细胞浸润。这些小鼠受影响的皮肤表现为抗微生物肽、趋化因子和细胞因子（包括辅助性 T 细胞 17 细胞特征性细胞因子）的表达升高，以及富含中性粒细胞、髓样细胞和 T 细胞的免疫浸润，类似于人类银屑病皮肤。疾病的发病机制是由 IL-23/IL-17 轴驱动的，中和 IL-23p19（维持辅助性 T 细胞 17 极化的关键细胞因子）可显著减少皮肤损伤和抗菌肽及促炎细胞因子的表达。因此，CARD14 的过度激活本身足以在体内协调驱动辅助性 T 细胞 17 介导的银屑病皮肤疾病的复杂免疫发病机制。
