TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target

Ullah, Mujeeb; Sweet, Matthew J.; Mansell, Ashley; Kellie, Stuart; Kobe, Boštjan

doi:10.1189/jlb.2ri1115-531r

Cited by 150 publications

(113 citation statements)

References 239 publications

(311 reference statements)

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“…TRIF is activated downstream of TLR3 and TLR4, which sense double-stranded RNA (dsRNA) or lipopolysaccharide (LPS), respectively. Analogously to TNFR1, signaling through either of these TLRs normally leads to pro-inflammatory and pro-survival responses in the cell due to NF-κB and IRF-3 activation (41), but when cells are sensitized to necroptosis by inhibition of capase-8/cFLIP, TRIF can activate RIPK1 and/or RIPK3. Notably, because TRIF contains a RHIM domain, it can directly activate RIPK3 in the absence of RIPK1 (39, 40); however, RIPK1 can also be recruited to TRIF (42), and this recruitment may alter the outcome of TRIF-RIPK3 signaling by promoting transcriptional responses and engaging the inhibitory effects of caspase-8 and cFLIP (recall that the latter depend on the DD of RIPK1 for recruitment).…”

Section: Ripk3-dependent Necroptosis: the “Canonical” Function Of Ripk3mentioning

confidence: 99%

RIPK3 in cell death and inflammation: the good, the bad, and the ugly

Orozco

Oberst

2017

Immunological Reviews

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Summary Necroptosis is a form of cell death that can be observed downstream of death receptor or pattern recognition receptor signaling under certain cellular contexts, or in response to some viral and bacterial infections. The receptor interacting protein kinases-1 (RIPK1) and RIPK3 are at the core of necroptotic signaling, among other proteins. Because this pathway is normally halted by the pro-apoptotic protease caspase-8 and the IAP ubiquitin ligases, how and when necroptosis is triggered in physiological settings are ongoing questions. Interestingly, accumulating evidence suggests that RIPK3 has functions beyond the induction of necroptotic cell death, especially in the areas of tissue injury and sterile inflammation. Here, we will discuss the role of RIPK3 in a variety of physiological conditions, including necroptotic and non-necroptotic cell death, in the context of viral and bacterial infections, tissue damage, and inflammation.

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Section: Ripk3-dependent Necroptosis: the “Canonical” Function Of Ripk3mentioning

confidence: 99%

RIPK3 in cell death and inflammation: the good, the bad, and the ugly

Orozco

Oberst

2017

Immunological Reviews

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“…TRIF-inducing stimuli may possess immunotherapeutic potential beyond direct antiviral activity (91–93). For instance, the TLR3/TRIF agonist poly(I-C) shows beneficial effects in mouse models of arthritis (94), colitis (95), bacterial infection (96), and wound healing (97, 98).…”

Section: Discussionmentioning

confidence: 99%

A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

Pryke

Abraham

Sali

et al. 2017

mBio

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The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity.

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“…Recent studies have suggested that the TRIF‐dependent signaling pathway of TLRs plays a central role in inflammatory responses such as viral infection and several chronic diseases (Ullah, Sweet, Mansell, Kellie, & Kobe, ). This is the first report that EPA can regulate TRIF‐dependent pathways of TLRs by targeting TBK1.…”

Section: Discussionmentioning

confidence: 99%

Eicosapentaenoic acid suppresses TRIF-dependent signaling pathway of TLRs by targeting TBK1

et al. 2017

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Toll-like receptors (TLRs) induce an innate immune system. In general, there are two main pathways in TLRs: the myeloid differentiation primary response protein 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-b (TRIF)-dependent pathways. In this study, it has been investigated whether eicosapentaenoic acid (EPA), a polyunsaturated fatty acid (PUFA), and arachidic acid (ACA), a saturated fatty acid (SFA), can modulate the TLR signaling pathways. EPA suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of Interferon gamma-induced protein (IP-10) induced by Toll-like receptor 3 (TLR3) or TLR4 agonists by targeting TANK-binding kinase 1 (TBK1); however, ACA did not. These results demonstrate that EPA inhibits the TRIF-dependent signaling in the TLR3 and TLR4 pathways. The results raise the possibility that certain dietary PUFAs can modulate TLR-derived signaling and inflammatory target gene expression and can alter the susceptibility to microbial infection and chronic inflammatory diseases. Practical applicationEicosapentaenoic acid (EPA) is a bioactive lipid that modulates inflammation and immunity. TLRs play a central role as initiators of the innate immune responses. EPA regulates TRIF-dependent pathways of TLRs by targeting TBK1. EPA may be a useful strategy to understand the mechanism of antiinflammatory activities. K E Y W O R D Sarachidic acid, eicosapentaenoic acid, TBK1, Toll-like receptor, TRIF

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TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target

Cited by 150 publications

References 239 publications

RIPK3 in cell death and inflammation: the good, the bad, and the ugly

RIPK3 in cell death and inflammation: the good, the bad, and the ugly

A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

Eicosapentaenoic acid suppresses TRIF-dependent signaling pathway of TLRs by targeting TBK1

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