title: Reprogramming of murine macrophages through TLR2 confers viral resistance via TRAF3-mediated, enhanced interferon production.
abstract: The cell surface/endosomal Toll-like Receptors (TLRs) are instrumental in initiating immune responses to both bacteria and viruses. With the exception of TLR2, all TLRs and cytosolic RIG-I-like receptors (RLRs) with known virus-derived ligands induce type I interferons (IFNs) in macrophages or dendritic cells. Herein, we report that prior ligation of TLR2, an event previously shown to induce "homo" or "hetero" tolerance, strongly "primes" macrophages for increased Type I IFN production in response to subsequent TLR/RLR signaling. This occurs by increasing activation of the transcription factor, IFN Regulatory Factor-3 (IRF-3) that, in turn, leads to enhanced induction of IFN-β, while expression of other pro-inflammatory genes are suppressed (tolerized). In vitro or in vivo "priming" of murine macrophages with TLR2 ligands increase virus-mediated IFN induction and resistance to infection. This priming effect of TLR2 is mediated by the selective upregulation of the K63 ubiquitin ligase, TRAF3. Thus, we provide a mechanistic explanation for the observed antiviral actions of MyD88-dependent TLR2 and further define the role of TRAF3 in viral innate immunity.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Perkins
authors.forename: Swamy K
authors.initials: SK
authors.lastname: Polumuri
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Pennini
authors.forename: Wendy
authors.initials: W
authors.lastname: Lai
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014616:Vaccinia virus / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: D007370:Interferon Type I; D008024:Ligands; D011994:Recombinant Proteins; D048008:TNF Receptor-Associated Factor 3; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2