Intracellular virus sensor MDA5 exacerbates vitiligo by inducing the secretion of chemokines in keratinocytes under virus invasion
Intracellular virus sensor MDA5 exacerbates vitiligo by inducing the secretion of chemokines in keratinocytes under virus invasion
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细胞内病毒传感器MDA5在病毒入侵下通过诱导角质形成细胞分泌趋化因子加剧白癜风
DOI：
10.1038/s41419-020-2665-z
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发表时间：
2020-06-12
影响因子：
9
通讯作者：
Li，Chunying
中科院分区：
文献类型：
--
作者：
Zhuang，Tongtian;Yi，Xiuli;Li，Chunying
白癜风是一种毁容性疾病，其特征是趋化因子介导的皮肤浸润的自身反应性CD8+T细胞杀死黑素细胞。大量研究表明，病毒入侵参与了白癜风的发病过程。编码细胞内病毒传感器MDA5的IFIH1已被确定为白癜风易感基因。然而，MDA5在病毒侵袭下黑素细胞死亡中的具体作用尚不清楚。在这项研究中，我们首次发现白癜风患者中抗cmv IgM和MDA5的表达高于健康对照组。然后，通过Poly（I:C）模拟病毒入侵，我们明确了病毒入侵可显著激活MDA5，并进一步增强角化细胞来源的CXCL10和CXCL16，这是白癜风中CD8+T细胞皮肤浸润的两个重要趋化因子。更重要的是，MDA5-MAVS-NF-κB/IRF3信号通路介导的IFN-β通过JAK1-STAT1通路介导CXCL10的分泌，mda5介导的IRF3转录诱导病毒侵袭下角质形成细胞中CXCL16的产生。总之，我们的研究结果表明MDA5信号通过介导CXCL10和CXCL16的分泌来协调参与黑素细胞死亡的异常皮肤免疫，这支持MDA5作为病毒入侵下白癜风的潜在治疗靶点。
Vitiligo is a disfiguring disease featuring chemokines-mediated cutaneous infiltration of autoreactive CD8+T cells that kill melanocytes. Copious studies have indicated that virus invasion participates in the pathogenesis of vitiligo.IFIH1, encoding MDA5 which is an intracellular virus sensor, has been identified as a vitiligo susceptibility gene. However, the specific role of MDA5 in melanocyte death under virus invasion is not clear. In this study, we first showed that the expression of anti-CMV IgM and MDA5 was higher in vitiligo patients than healthy controls. Then, by using Poly(I:C) to imitate virus invasion, we clarified that virus invasion significantly activated MDA5 and further potentiated the keratinocyte-derived CXCL10 and CXCL16 which are the two vital chemokines for the cutaneous infiltration of CD8+T cells in vitiligo. More importantly, IFN-β mediated by the MDA5-MAVS-NF-κB/IRF3 signaling pathway orchestrated the secretion of CXCL10 via the JAK1-STAT1 pathway and MDA5-meidiated IRF3 transcriptionally induced the production of CXCL16 in keratinocytes under virus invasion. In summary, our results demonstrate that MDA5 signaling orchestrates the aberrant skin immunity engaging in melanocyte death via mediating CXCL10 and CXCL16 secretion, which supports MDA5 as a potential therapeutic target for vitiligo under virus invasion.