title: Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner.
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 toP. gingivalis; full reactivity toP. 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 toP. 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.
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany.|Center for Dental and Oral Medicine, Department of Periodontology, Operative and Preventive Dentistry, University Hospital Bonn, Bonn, Germany.
authors: Tobias
authors: T
authors: Waller
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany.
authors: Laura
authors: L
authors: Kesper
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany.|Center for Dental and Oral Medicine, Department of Periodontology, Operative and Preventive Dentistry, University Hospital Bonn, Bonn, Germany.
authors: Josefine
authors: J
authors: Hirschfeld
authors: Center for Dental and Oral Medicine, Department of Periodontology, Operative and Preventive Dentistry, University Hospital Bonn, Bonn, Germany.|Institute for Dental and Oral Medicine, Department of Periodontology and Synoptic Dentistry, Charité Berlin, Berlin, Germany.
authors: Henrik
authors: H
authors: Dommisch
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany.
authors: Johanna
authors: J
authors: Kölpin
authors: Institute for Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany.
authors: Johannes
authors: J
authors: Oldenburg
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany.|Division of Microbiology, Paul-Ehrlich Institute, Langen, Germany.
authors: Julia
authors: J
authors: Uebele
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany.
authors: Achim
authors: A
authors: Hoerauf
authors: Center for Dental and Oral Medicine, Department of Experimental Dento-Maxillo-Facial Medicine, University Hospital Bonn, Bonn, Germany.
authors: James
authors: J
authors: Deschner
authors: Center for Dental and Oral Medicine, Department of Periodontology, Operative and Preventive Dentistry, University Hospital Bonn, Bonn, Germany.
authors: Sören
authors: S
authors: Jepsen
authors: Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany isabelle.bekeredjian-ding@pei.de.|Division of Microbiology, Paul-Ehrlich Institute, Langen, Germany.
authors: Isabelle
authors: I
authors: Bekeredjian-Ding
mesh_terms: D002462:Cell Membrane; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases