Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A
Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A
复制标题
Card14 的功能获得突变通过增强角质形成细胞对 IL-17A 的反应导致自发性银屑病样皮肤炎症
DOI：
10.1016/j.immuni.2018.05.012
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发表时间：
2018-07-17
期刊：
影响因子：
32.4
通讯作者：
Xin Lin
中科院分区：
文献类型：
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作者：
Wang, Mingchao;Zhang, Shanshan;Xin Lin
在银屑病患者中观察到CARD 14（编码CARMA 2）的基因突变。在这里，我们发现Card 14（E138 A/+）和Card 14（Delta Q136/+）小鼠发生自发性银屑病样皮肤炎症，这是由组成性激活的CARMA 2通过自聚集导致IL-23-IL-17 A细胞因子轴的增强激活引起的。Card 14（-/-）小鼠在咪喹莫特诱导的银屑病模型中显示出减弱的皮肤炎症，这是由于角质形成细胞中IL-17 A信号传导受损。CARMA 2主要在角质形成细胞中表达，与ACT 1-TRAF 6信号传导复合物相关，并介导IL-17 A诱导的NF-κ B和MAPK信号传导途径活化，从而导致促炎因子的表达。因此，CARMA 2作为IL-17 A信号传导的关键介质，其在角质形成细胞中的组成性活化导致银屑病的发作，这表明角质形成细胞中NF-κ B活化在银屑病起始中的重要作用。
Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14(E138A/+) and Card14(Delta Q136/+) mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14(-/-) mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-kappa B and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors. Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-kappa B activation in keratinocytes in psoriatic initiation.