TLR9 is actively recruited to Aspergillus fumigatus phagosomes and requires the N-terminal proteolytic cleavage domain for proper intracellular trafficking.
TLR9 is actively recruited to Aspergillus fumigatus phagosomes and requires the N-terminal proteolytic cleavage domain for proper intracellular trafficking.
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DOI：
10.4049/jimmunol.1002760
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发表时间：
2010-12-15
期刊：
影响因子：
--
通讯作者：
Vyas JM
中科院分区：
文献类型：
--
作者：
Kasperkovitz PV;Cardenas ML;Vyas JM
toll样受体9 （TLR9）识别未甲基化的CpG DNA并诱导先天免疫反应。TLR9激活是一个多步骤的过程，需要蛋白水解裂解和运输到内溶酶体室，以获得配体诱导的信号。然而，控制TLR9在病原体摄取后动态亚细胞运输的规则尚未确定。在这项研究中，我们证明了在小鼠巨噬细胞中，烟曲霉（Aspergillus fumigatus, Af）分生孢子的摄取诱导了TLR9在含Af吞噬体的吞噬体膜上的剧烈空间重新分布，而不是在含珠的吞噬体上。在不同萌发阶段的Af孢子和影响抗原在真菌细胞表面显示的选定突变体中，TLR9特异性募集到真菌吞噬体是一致的。TLR9向吞噬小体区隔的时空调控不依赖于TLR2、TLR4和下游TLR信号。我们的数据表明，TLR9 n端蛋白水解切割结构域对于TLR9在含cpg的区室和af吞噬体膜上成功的细胞内运输和积累至关重要。我们的研究为巨噬细胞吞噬心房孢子特异性诱导TLR9募集到心房吞噬体的模型提供了证据，从而可能介导TLR9诱导的抗真菌先天免疫反应。
Toll-like receptor 9 (TLR9) recognizes unmethylated CpG DNA and induces innate immune responses. TLR9 activation is a multistep process requiring proteolytic cleavage and trafficking to endolysosomal compartments for ligand-induced signaling. However, the rules that govern the dynamic subcellular trafficking for TLR9 after pathogen uptake have not been established. In this study, we demonstrate that uptake of Aspergillus fumigatus (Af) conidia induced drastic spatial redistribution of TLR9 to the phagosomal membrane of Af-containing phagosomes but not to bead-containing phagosomes in murine macrophages. Specific TLR9 recruitment to the fungal phagosome was consistent using Af spores at different germination stages and selected mutants affecting the display of antigens on the fungal cell surface. Spatiotemporal regulation of TLR9 compartmentalization to the Af phagosome was independent of TLR2, TLR4 and downstream TLR signaling. Our data demonstrate that the TLR9 N-terminal proteolytic cleavage domain was critical for successful intracellular trafficking and accumulation of TLR9 in CpG-containing compartments and Af-phagosomal membranes. Our study provides evidence for a model in which Af spore phagocytosis by macrophages specifically induces TLR9 recruitment to Af phagosomes and may thereby mediate TLR9-induced antifungal innate immune responses.
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