title: TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1-IKKβ-IRF5 Signaling Pathway.
abstract: Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus and elicits production of proinflammatory cytokines via MyD88 -: NF-κB signaling. S. aureus can also induce the production of IFN-β, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-β induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-β production but instead can suppress the induction of IFN-β in human primary monocytes and monocyte-derived macrophages. The production of IFN-β was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and IκB kinase (IKK)β, which thus reveals a physiological role of the recently described IRF5-activating function of IKKβ. TLR8 -: IRF5 signaling was necessary for induction of IFN-β and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-β and IL-12 production via a TAK1 -: IKKβ -: IRF5 pathway that can be inhibited by TLR2 signaling.
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Bjarte
authors.initials: B
authors.lastname: Bergstrøm
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Marie H
authors.initials: MH
authors.lastname: Aune
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Jane A
authors.initials: JA
authors.lastname: Awuh
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: June F
authors.initials: JF
authors.lastname: Kojen
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Kjetil J
authors.initials: KJ
authors.lastname: Blix
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Liv
authors.initials: L
authors.lastname: Ryan
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Trude H
authors.initials: TH
authors.lastname: Flo
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway; Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo N-0027, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo N-0027, Norway; Research Laboratory, Nordland Hospital, Bodø N-8092, Norway; and Institute of Clinical Medicine, University of Tromsø, Tromsø N-9037, Norway.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway; jorgen.stenvik@ntnu.no.
authors.forename: Jørgen
authors.identifier: http://orcid.org/0000-0002-1051-9258
authors.initials: J
authors.lastname: Stenvik
mesh_terms: D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics; D009000:Monocytes / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034622:RNA Interference; D012329:RNA, Bacterial / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099151:MAP Kinase Kinase Kinase 7; D000099197:STING Protein
chemical_list: D051550:I-kappa B Kinase; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D018664:Interleukin-12; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D012329:RNA, Bacterial; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C431713:IRF5 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C495342:TLR2 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C439524:TNF protein, human; C403191:TBK1 protein, human; C496560:IKBKB protein, human