TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells
TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells
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DOI：
10.4049/jimmunol.0903736
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发表时间：
2010-09-15
影响因子：
4.4
通讯作者：
Gosselin, Jean
中科院分区：
文献类型：
--
作者：
Fiola, Stephanie;Gosselin, David;Gosselin, Jean
TLR9 通过检测细胞内外源 DNA 的 CpG 基序，在针对病毒的先天防御中发挥重要作用。在本研究中，我们评估了 EBV 通过 TLR9 激活促进单核细胞和浆细胞样树突状细胞 (pDC) 激活和细胞因子释放的能力。我们证明，用 EBV 和纯化的 EBV DNA 处理原代单核细胞可通过 TLR9 诱导 IL-8 的释放。病毒 DNA 激活 TLR9 需要内体成熟，因为用氯喹预处理单核细胞会强烈减少 IL-8 的分泌。然而，用针对 TLR2 的 siRNA、抑制性 ODN (iODN) 或两种抑制剂的组合对单核细胞进行预处理，大大减少了 IL-8 的分泌，这提供了 TLR2 和 TLR9 在单核细胞识别 EBV 中双重作用的证据。相反，EBV处理的单核细胞中MCP-1和IL-10的产生主要通过TLR2调节。尽管 EBV 不会在 pDC 中建立感染，但发现用活 EBV 颗粒或分离的 EBV DNA 攻击可诱导通过 TLR9 释放 IFN-α，这一点得到了用 iODN 或氯喹阻断 TLR9 活性的支持。 TLR9 在 pDC 识别 EBV 中的作用似乎占主导地位，观察到 iODN 对 pDC 合成 IFN-α、IL-6 和 IL-8 的显着抑制作用证实了这一点。这些结果表明，TLR9 对 EBV 的识别在原代单核细胞和 pDC 中进行了不同的协调，以优化病毒识别和抗病毒反应。免疫学杂志，2010，185：3620-3631。
TLR9 plays an important role in innate defense against viruses by the detection of CpG motifs of foreign DNA within intracellular compartments. In this study, we evaluated the ability of EBV to promote monocyte and plasmacytoid dendritic cell (pDC) activation and cytokine release through TLR9 activation. We demonstrated that treatment of primary monocytes with EBV and with purified EBV DNA induced the release of IL-8 through TLR9. Activation of TLR9 by viral DNA requires endosomal maturation because pretreatment of monocytes with chloroquine strongly reduced IL-8 secretion. However, pretreatment of monocytes with siRNA directed against TLR2, with inhibitory ODN (iODN) or with a combination of both inhibitors strongly reduced the secretion of IL-8, providing evidence of a dual action of TLR2 and TLR9 in EBV recognition by monocytes. In contrast, production of MCP-1 and IL-10 in EBV-treated monocytes was mainly regulated through TLR2. Although EBV does not establish infection in pDCs, challenge with either live EBV particles or isolated EBV DNA was found to induce the release of IFN-alpha through TLR9, as supported by blockage of TLR9 activity with iODN or chloroquine. The role of TLR9 in the recognition of EBV by pDCs appears to be dominant, as confirmed by the marked inhibitory effect of iODN observed on the synthesis of IFN-alpha, IL-6, and IL-8 by pDCs. These results demonstrate that recognition of EBV by TLR9 is differently orchestrated in primary monocytes and pDCs to optimize viral recognition and antiviral response. The Journal of Immunology, 2010, 185: 3620-3631.