The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-β production
The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-β production
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DOI：
10.4049/jimmunol.181.8.5522
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发表时间：
2008-10-15
影响因子：
4.4
通讯作者：
Matsumoto, Misako
中科院分区：
文献类型：
--
作者：
Itoh, Kiyoharu;Watanabe, Ayako;Matsumoto, Misako
TLR 3和细胞质RIG-I样受体（RLR）识别病毒衍生的dsRNA并以不同的方式诱导I型IFN产生。人TLR 3定位于髓样树突状细胞（mDC）中的内体区室，而其定位于成纤维细胞和上皮细胞中的细胞表面和内部。TLR 3信号传导在两种细胞类型的细胞内区室中产生，并且需要内体成熟。细胞外dsRNA被递送到含有TLR 3的细胞器的机制在很大程度上仍然未知。在各种合成的dsRNA中，poly（I：C）优先内化并激活mDC中的TLR 3。体外转录的dsRNA几乎不诱导mDC中的IFN-β产生。在这项研究中，我们证明，网格蛋白依赖的内吞途径介导的细胞进入的聚（I：C）诱导IFN-β基因转录。此外，用B型和C型寡脱氧核苷酸（ODNs）预处理细胞可抑制聚（I：C）诱导的IFN-β产生，但用TLR 7/8配体则不抑制。在poly（I：C）存在下，mDCs对B型ODN的结合和内化减少，表明poly（I：C）与B型和C型ODN共享摄取受体。因此，外源dsRNA被不同分类的受体、细胞质RIG-I样受体、膜结合的TLR 3和细胞表面RNA捕获识别。内吞途径对于dsRNA诱导的TLR 3介导的细胞活化至关重要。
TLR3 and cytoplasmic RIG-I-like receptor (RLR) recognize virus-derived dsRNA and induce type I IFN production in a distinct manner. Human TLR3 localizes to the endosomal compartments in myeloid dendritic cells (mDCs), while it localizes to both the cell surface and interior in fibroblasts and epithelial cells. TLR3 signaling arises in the intracellular compartment in both cell types and requires endosomal maturation. The mechanisms by which extracellular dsRNA is delivered to the TLR3-containing organelle remain largely unknown. Among various synthetic dsRNAs, poly(I:C) is preferentially internalized and activates TLR3 in mDCs. In vitro transcribed dsRNAs hardly induce IFN-beta production in mDCs. In this study, we demonstrate that the clathrin-dependent endocytic pathway mediates cell entry of poly(I:C) to induce IFN-beta gene transcription. Furthermore, poly(I:C)-induced IFN-beta production is inhibited by pretreatment of cells with B- and C-type oligodeoxynucleotides (ODNs) but not with TLR7/8 ligands. The binding and internalization of B-type ODNs by mDCs was reduced in the presence of poly(I:C), suggesting that poly(I:C) shares the uptake receptor with B- and C-type ODNs. Hence, foreign dsRNA is recognized by differently categorized receptors, cytoplasmic RIG-I-like receptor, membrane-bound TLR3 and cell-surface RNA capture. The endocytic pathway is critical for dsRNA-induced TLR3-mediated cell activation.