Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-Mediated differential signaling
Double-stranded RNA induces an antiviral defense status in epidermal keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-Mediated differential signaling
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DOI：
10.4049/jimmunol.181.4.2694
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发表时间：
2008-08-15
影响因子：
4.4
通讯作者：
Ollert, Markus
中科院分区：
文献类型：
--
作者：
Kalali, Behnam Naderi;Koellisch, Gabriele;Ollert, Markus
新出现的证据表明，人表皮角质形成细胞在先天免疫机制中对细菌和病毒皮肤感染的重要作用。病毒感染的促炎作用可以通过双链RNA（dsRNA）模拟。在此，我们证明角质形成细胞在组成型和诱导型水平表达所有已知的dsRNA传感受体，并且它们使用几种下游信号传导途径导致广泛的基因表达模式，不仅是NF-κ B控制下的促炎和免疫应答基因，而且是IRF 3转录控制下的基因。因此，dsRNA，刺激TLR 3，蛋白激酶R（PKR）和RNA解旋酶;视黄酸诱导基因I（RIG-I）和MDA 5，诱导角质形成细胞的抗病毒防御状态。使用各种dsRNA信号通路的抑制剂和TLR 3、RIG-I和MDA 5的特异性小干扰RNA，我们证明了在人角质形成细胞中，TLR 3似乎是NF-κ B B激活所必需的，但不是IRF 3激活所必需的，而RIG-I和MDA 5是IRF 3激活所必需的。PKR对于两种信号传导途径中的dsRNA应答是必不可少的，因此代表了dsRNA刺激的中心抗病毒受体。此外，人角质形成细胞上调TLR 7，单链RNA的受体，以响应dsRNA的刺激，这使得角质形成细胞在功能上响应TLR 7激动剂gardiquimod，咪唑并喹啉抗病毒免疫应答调节剂家族的成员。因此，除了建立针对感染性病原体的物理屏障外，角质形成细胞还特别配备了完整的抗病毒防御程序，使其能够有效地靶向皮肤的病毒感染。
Emerging evidence suggests an important role for human epidermal keratinocytes in innate immune mechanisms against bacterial and viral skin infections. The proinflammatory effect of viral infections can be mimicked by double-stranded RNA (dsRNA). Herein, we demonstrate that keratinocytes express all known dsRNA sensing receptors at a constitutive and inducible level, and that they use several downstream signaling pathways leading to a broad pattern of gene expression, not only proinflammatory and immune response genes under the control of NF-kappa B, but also genes under transcriptional control of IRF3. As a consequence, dsRNA, a stimulus for TLR3, protein kinase R (PKR), and the RNA helicases; retinoic acid-inducible gene I (RIG-I) and MDA5, induces a status of antiviral defense in keratinocytes. Using inhibitors for the various dsRNA signaling pathways and specific small interfering RNA for TLR3, RIG-I, and MDA5, we demonstrated that in human keratinocytes, TLR3 seems to be necessary for NF-kappa B but not for IRF3 activation, whereas RIG-I and MDA5 are crucial for IRF3 activation. PKR is essential for the dsRNA response in both signaling pathways and thus represents the central antiviral receptor for dsRNA stimulation. Moreover, human keratinocytes up-regulate TLR7, the receptor for single-stranded RNA, in response to stimulation with dsRNA, which renders keratinocytes functionally responsive to the TLR7 agonist gardiquimod, a member of the imidazoquinoline antiviral immune response modifier family. Thus, in addition to building a physical barrier against infectious pathogens, keratinocytes; are specially equipped with a full antiviral defense program that enables them to efficiently target viral infections of the skin.