Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner
Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner
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角质形成细胞的内在异常通过 IL-23/T17 轴以 MALT1 依赖性方式引发皮肤炎症
DOI：
10.4049/jimmunol.2001031
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发表时间：
2021-02-15
影响因子：
4.4
通讯作者：
Zhao, Xueqiang
中科院分区：
文献类型：
--
作者：
Zhang, Shanshan;Wang, Mingchao;Zhao, Xueqiang
关键点IL-23/T17轴的消融抑制了Card 14 E138 A/+小鼠的皮肤炎症。角质形成细胞中的CBM复合物引发银屑病样皮肤炎症。MALT 1 paracaspase活性可能是银屑病治疗的一个有前途的靶点。越来越多的证据支持CARD 14在银屑病发病机制中的关键作用，而参与皮肤病理生理学的精确细胞信号传导仍然知之甚少。在这篇文章中，我们表明，在CARD 14-E138 A突变诱导的银屑病样小鼠模型中，IL 17 a的基因消融和T细胞的消除都不足以抑制皮肤炎症，而IL-23/T17轴的极度阻断的IL-23/T17轴的消耗更有效。通过在角质形成细胞中条件性缺失MALT 1或BCL 10来靶向CBM复合物，消除了杂合Card 14 E138 A/+小鼠的皮肤和全身炎症。角质形成细胞特异性MALT 1蛋白水解活性的选择性失活强烈改善了Card 14 E138 A/+-和Card 14 ΔQ136/+-诱导的皮肤病，这通过使用咪喹莫特诱导的小鼠模型再现。总之，我们的结果表明，在CARD 14突变诱导的银屑病条件下，角质形成细胞固有的CBM复合物激活会根据IL-23/T17轴引发皮肤炎症，这是一系列事件。通过灭活MALT 1 paracaspase活性靶向角质形成细胞可能是早期银屑病治疗的一个有前途的治疗靶点。
Key Points Ablation of the IL-23/T17 axis restrains the skin inflammation in Card14E138A/+ mice. CBM complex in keratinocyte initiates psoriasis-like skin inflammation. MALT1 paracaspase activity could be a promising therapeutic target for psoriasis. Increasing evidence has supported the crucial role of CARD14 in the pathogenesis of psoriasis, whereas the precise cellular signaling involved in skin physiopathology remains poorly understood. In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14E138A/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14E138A/+- and Card14ΔQ136/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.