Both TLR2 and TRIF Contribute to Interferon-β Production during Listeria Infection

University of São Paulo, Brazil
PLoS ONE (Impact Factor: 3.53). 03/2012; 7(3):e33299. DOI: 10.1371/journal.pone.0033299
Source: PubMed

ABSTRACT Synthesis of interferon-β (IFN-β) is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-β synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-β production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, ΔpgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-β gene, requiring TLR2 and bacterial internalization. Induction of IFN-β was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-β gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-β gene expression.

  • 01/2014; 1. DOI:10.2478/immun-2014-0001
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    ABSTRACT: Type I interferons (IFNs) were first described for their ability to protect the host from viral infections and may also have beneficial effects under specific conditions within some bacterial infections. Yet, these pleiotropic cytokines are now known to exacerbate infections by numerous life-threatening bacteria, including the intracellular pathogens Listeria monocytogenes and Mycobacterium tuberculosis. The evidence that such detrimental effects occur during bacterial infections in both animals and humans argues for selective pressure. In this review, we summarize the evidence demonstrating a pro-bacterial role for type I IFNs and discuss possible mechanisms that have been proposed to explain such effects. The theme emerges that type I IFNs act to suppress myeloid cell immune responses. The evolutionary conservation of such anti-inflammatory effects, particularly in the context of infections, suggests they may be important for limiting chronic inflammation. Given the effectiveness of type I IFNs in treatment of certain autoimmune diseases, their production may also act to raise the threshold for activation of immune responses to self-antigens.
    Frontiers in Immunology 09/2014; 5:431. DOI:10.3389/fimmu.2014.00431
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    ABSTRACT: Toll-like receptors (TLRs) are receptors involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, while lipopolysaccharide (LPS) activates TLR4. TLR2 and TLR4 signal via the Toll/Interleukin-1 receptor (TIR) adaptors MyD88 and MAL, leading to NF-κB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF)3. Here we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine CCL5 was impaired in TRAM-/- or TRIF-/- macrophages. Inhibition of endocytosis reduced CCL5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. CCL5 release following lipoprotein challenge additionally involved the kinase TBK-1 and IRF3, as well as MyD88 and IRF1. Induction of interferon-β and CCL4 by lipoproteins were also partially impaired in TRIF-/- cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how TIR adaptor proteins may participate in signaling downstream from TLR2. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; DOI:10.1074/jbc.M114.593426 · 4.60 Impact Factor

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