Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner
Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner
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DOI：
10.1128/iai.01390-15
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发表时间：
2016-02
影响因子：
3.1
通讯作者：
Tobias Waller;Laura Kesper;J. Hirschfeld;H. Dommisch;Johanna Kölpin;J. Oldenburg;Julia Uebele;A. Hoerauf;J. Deschner;S. Jepsen;I. Bekeredjian-Ding
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文献类型：
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作者：
Tobias Waller;Laura Kesper;J. Hirschfeld;H. Dommisch;Johanna Kölpin;J. Oldenburg;Julia Uebele;A. Hoerauf;J. Deschner;S. Jepsen;I. Bekeredjian-Ding
牙龈卟啉单胞菌是口腔厌氧植物群的重要成员。它的存在促进牙周生物膜的生长和牙周炎的发展。在这项研究中，我们证明了牙龈卟啉单胞菌脱落的亲脂性外膜囊泡（OMV）促进单核细胞对活牙龈卟啉单胞菌的无反应性，但保留对从牙龈卟啉单胞菌或AIM 2配体poly（dA·dT）分离的细菌DNA刺激的反应性。OMV介导的牙龈卟啉单胞菌耐受的特征在于选择性消除肿瘤坏死因子（TNF）。OMV激发期间白细胞介素-10（IL-10）的中和部分恢复单核细胞对牙龈卟啉单胞菌的反应性;对牙龈卟啉单胞菌的完全反应性可以通过抑制mTOR信号传导来恢复，我们先前将其确定为促进单核细胞中Toll样受体2和Toll样受体4（TLR 2/4）介导的耐受性的主要信号传导途径。然而，尽管先前的报道强调了TLR 2在牙龈卟啉单胞菌的先天免疫识别中的核心作用，但我们目前的研究结果强调了TLR 4在促进OMV介导的TNF耐受性中的选择性作用：仅阻断TLR 4-而不是TLR 2-恢复对牙龈卟啉单胞菌的反应性。进一步注意到，OMV介导的耐受性在细胞松弛素B和氯喹存在下得以保留，表明表面TLR 4的触发足以实现该效果。综合以上结果，我们认为牙龈卟啉单胞菌OMV通过阻碍宿主免疫应答而促进牙龈卟啉单胞菌的局部免疫逃避。
ABSTRACT Porphyromonas gingivalis is an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed from P. gingivalis promote monocyte unresponsiveness to live P. gingivalis but retain reactivity to stimulation with bacterial DNA isolated from P. gingivalis or AIM2 ligand poly(dA·dT). OMV-mediated tolerance of P. gingivalis is characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness to P. gingivalis; full reactivity to P. gingivalis can be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition of P. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4—and not of TLR2—restores responsiveness to P. gingivalis. Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose that P. gingivalis OMV contribute to local immune evasion of P. gingivalis by hampering the host response.