Reprogramming of Murine Macrophages through TLR2 Confers Viral Resistance via TRAF3-Mediated, Enhanced Interferon Production
Open Access
- 11 July 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 9 (7), e1003479
- https://doi.org/10.1371/journal.ppat.1003479
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. In response to viral infection, cells of the innate immune system synthesize and release members of the type I interferon protein family. The interferons form an essential line of defense, both by slowing viral growth and by expanding the cellular immune response. The synthesis of interferon is initiated by recognition of viral constituents by one or more innate receptors. Among these receptors, Toll like receptor 2 (TLR2) has been shown to be critical for the immune response to a number of viruses, yet TLR2 only directly initiates Type I interferon production in a very small set of innate immune cells. We have discovered that TLR 2 can contribute to the antiviral interferon response much more broadly by indirectly governing the production of interferon induced by other Toll like receptors as wells as downstream of the cytosolic Rig-I like receptors. This happens through the TLR2-dependent up-regulation of a critical signaling element, TRAF3. We also demonstrate that this TLR2 dependent regulation of interferon may be important in biological scenarios involving co-infection of virus and Gram positive bacteria, but not Gram negative bacteria.Keywords
This publication has 46 references indexed in Scilit:
- DDX1, DDX21, and DHX36 Helicases Form a Complex with the Adaptor Molecule TRIF to Sense dsRNA in Dendritic CellsImmunity, 2011
- Host Defense Pathways: Role of Redundancy and Compensation in Infectious Disease PhenotypesImmunity, 2011
- Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and ImmunityImmunity, 2011
- Facultative heterochromatin formation at the IL-1 beta promoter in LPS tolerance and sepsisCytokine, 2010
- Tumor Necrosis Factor Receptor-Associated Factor 3 Is a Critical Regulator of B Cell Homeostasis in Secondary Lymphoid OrgansImmunity, 2007
- Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune ResponseImmunity, 2006
- Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral responseNature, 2005
- Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6Nature, 2005
- Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3Cell, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001