CARD 14 gain‐of‐function mutations cause psoriasis in humans and mice. Together with BCL 10 and the protease MALT 1, mutant CARD 14 forms a signaling node that mediates increased NF ‐κB signaling and proinflammatory gene expression in keratinocytes. However, it remains unclear whether psoriasis in response to CARD 14 hyperactivation is keratinocyte‐intrinsic or requires CARD 14 signaling in other cells. Moreover, the in vivo effect of MALT 1 targeting on mutant CARD 14‐induced psoriasis has not yet been documented. Here, we show that inducible keratinocyte‐specific expression of CARD 14^E138A in mice rapidly induces epidermal thickening and inflammation as well as increased expression of several genes associated with psoriasis in humans. Keratinocyte‐specific MALT 1 deletion as well as oral treatment of mice with a specific MALT 1 protease inhibitor strongly reduces psoriatic skin disease in CARD 14^E138A mice. Together, these data illustrate a keratinocyte‐intrinsic causal role of enhanced CARD 14/MALT 1 signaling in the pathogenesis of psoriasis and show the potential of MALT 1 inhibition for the treatment of psoriasis.

中文翻译：

---

MALT1 靶向抑制 CARD14 诱导的小鼠银屑病皮炎。

CARD 14功能获得性突变导致人类和小鼠银屑病。与 BCL 10 和蛋白酶 MALT 1 一起，突变 CARD 14 形成一个信号节点，介导角质形成细胞中增加的 NF-κB 信号和促炎基因表达。然而，尚不清楚响应 CARD 14 过度激活的银屑病是角质形成细胞固有的还是需要其他细胞中的 CARD 14 信号传导。此外， MALT 1 靶向突变 CARD 14 诱导的银屑病的体内作用尚未得到证实。^{在这里，我们展示了 CARD 14 E138A}的可诱导角质形成细胞特异性表达在小鼠中迅速诱导表皮增厚和炎症，以及增加与人类银屑病相关的几种基因的表达。角质形成细胞特异性 MALT 1 缺失以及用特定 MALT 1 蛋白酶抑制剂口服治疗小鼠可显着降低 CARD 14 ^E138A小鼠的银屑病皮肤病。总之，这些数据说明了增强的 CARD 14/MALT 1 信号传导在牛皮癣发病机制中的内在因果作用，并显示了 MALT 1 抑制治疗牛皮癣的潜力。