Selective TRIF-Dependent Signaling by a Synthetic Toll-Like Receptor 4 Agonist

Bowen, William S.; Minns, Laurie A.; Johnson, David A.; Mitchell, Thomas C.; Hutton, Melinda M.; Evans, John K.

doi:10.1126/scisignal.2001963

Cited by 71 publications

(75 citation statements)

References 51 publications

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“…Although in the past, inclusion of lipid A in a vaccine was considered to be associated with an unacceptable rate of side effects, more recent work, however, suggests that the toxicity of lipid A largely depends on the species of bacteria; moreover, some chemical modifications may result in nontoxic compounds with high adjuvant activity (15,27). Studies have shown that the monophosphorylated nature of the MPL compound selectively activates the TRIF pathway of the TLR4 signaling cascade (28,29). However, it may be more beneficial for a lipid A compound to activate both TRIF and MyD88 pathways without the toxic proinflammatory side effects.…”

Section: Discussionmentioning

confidence: 99%

Activation of Innate Immune Responses by Haemophilus influenzae Lipooligosaccharide

Choi

Cox

et al. 2014

Clin. Vaccine Immunol.

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A Gram-negative pathogen Haemophilus influenzae has a truncated endotoxin known as lipooligosaccharide (LOS). Recent studies on H. influenzae LOS highlighted its structural and compositional implications for bacterial virulence; however, the role of LOS in the activation of innate and adaptive immunity is poorly understood. THP-1 monocytes were stimulated with either lipopolysaccharide (LPS) from Escherichia coli or LOS compounds derived from H. influenzae Eagan, Rd, and Rd lic1 lpsA strains. Cell surface expression of key antigen-presenting, costimulatory, and adhesion molecules, as well as gene expression of some cytokines and pattern recognition receptors, were studied. Eagan and Rd LOS had a lower capacity to induce the expression of ICAM-1, CD40, CD58, tumor necrosis factor alpha (TNF-␣), and interleukin-1␤ (IL-1␤) compared to LPS. In contrast, antigen-presenting (HLA-ABC or HLA-DR) and costimulatory (CD86) molecules and NOD2 were similarly upregulated in response to LOS and LPS. LOS from a mutant Rd strain (Rd lic1 lpsA) consistently induced higher expression of innate immune molecules than the wild-type LOS, suggesting the importance of phosphorylcholine and/or oligosaccharide extension in cellular responses to LOS. An LOS compound with a strong ability to upregulate antigen-presenting and costimulatory molecules combined with a low proinflammatory activity may be considered a vaccine candidate to immunize against H. influenzae.

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Section: Discussionmentioning

confidence: 99%

Activation of Innate Immune Responses by Haemophilus influenzae Lipooligosaccharide

Choi

Cox

et al. 2014

Clin. Vaccine Immunol.

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“…This pathway, which is dependent on two adaptors, TRIF (TIR domain-containing adapter-inducing beta interferon) and TRAM (TRIF-related adaptor molecule), activates the transcription factors interferon regulatory factor 3 (IRF3) and IRF7, leading to the production of type 1 interferon (IFN) (28). Generally, while the TRIF pathway is involved in type I interferon response, the MyD88-dependent pathway triggers essentially inflammatory cytokines (29). Downstream of the MyD88 and TRIF pathways, several studies have reported the implication of MAP kinases, NF-B, and the serine/threonine kinases protein kinase C epsilon (PKC-ε), PKC-␦, PKC-, and PKC-in TLR4 signaling (30)(31)(32).…”

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confidence: 99%

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

Planès

Haij

Leghmari

et al. 2016

J Virol

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In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-␣) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Therefore, this study analyzed whether the HIV-1 Tat protein is able to activate these two pathways separately or simultaneously. Using three complementary approaches, including mice deficient in the MyD88, TIRAP/MAL, or TRIF adaptor, biochemical analysis, and the use of specific small interfering RNAs (siRNAs), we demonstrated (i) that Tat was able to activate both the MyD88 and TRIF pathways, (ii) the capacity of Tat to induce TIRAP/MAL degradation, (iii) the crucial role of the MyD88 pathway in the production of Tat-induced TNF-␣ and IL-10, (iv) a reduction but not abrogation of IL-10 and TNF-␣ by Tat-stimulated macrophages from mice deficient in TIRAP/MAL, and (v) the crucial role of the TRIF pathway in Tat-induced IL-10 production. Further, we showed that downstream of the MyD88 and TRIF pathways, the Tat protein activated the protein kinase C (PKC) ␤II isoform, the mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-B in a TLR4-dependent manner. Collectively, our data show that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC, MAP kinase, and NF-B signaling to induce the production of TNF-␣ and IL-10. IMPORTANCEIn this study, we demonstrate that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC-␤II, MAP kinase, and NF-B signaling to induce the production of TNF-␣ and IL-10, two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Thus, it may be interesting to target Tat as a pathogenic factor early after HIV-1 infection. This could be achieved either by vaccination approaches including Tat as an immunogen in potential candidate vaccines or by developing molecules capable of neutralizing the effect of the Tat protein.

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“…Several studies have focused on modulation of TLR4 signaling (39,40), and TICAM-1-specific TLR4 agonists were recently generated (39,41). Although switching the molecular relationship between TLR4 and TIRAP or TICAM-2 is an attractive strategy for control of bacterial pathogenesis (39)(40)(41), it is difficult to achieve specific regulation discriminating between the MyD88-TIRAP and TICAM-1-TICAM-2 pathways without cell damage in vivo by the currently available methods.…”

Section: Discussionmentioning

confidence: 99%

“…Although switching the molecular relationship between TLR4 and TIRAP or TICAM-2 is an attractive strategy for control of bacterial pathogenesis (39)(40)(41), it is difficult to achieve specific regulation discriminating between the MyD88-TIRAP and TICAM-1-TICAM-2 pathways without cell damage in vivo by the currently available methods. TICAM-1 harbors potential to activate multifarious intracellular signaling pathways that evoke live and death events in cells with TLR3 stimulation (27,42,43).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Regulatory Acidic Motif as the Determinant of Membrane Localization of TICAM-2

Funami

Matsumoto

Enokizono

et al. 2015

The Journal of Immunology

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TLR4 triggers LPS signaling through the adaptors Toll/IL-1R domain–containing adaptor molecule (TICAM)-2 (also called TRAM) and TICAM-1 (also called TRIF), together with Toll/IL-1R domain–containing adaptor protein (TIRAP) and MyD88. The MyD88 pathway mediates early phase responses to LPS on the plasma membrane, whereas the TICAM pathway mediates late-phase responses, which induce the production of type I IFN and activation of inflammasomes. TICAM-2 bridges TLR4 and TICAM-1 for LPS signaling in the endosome. Recently, we identified an acidic motif, E87/D88/D89 in TICAM-2, that provides the interaction surfaces between TICAM-2 and TICAM-1. In the present study, we found additional D91/E92 in TICAM-2, conserved across species, that is crucial for TICAM-1 activation. The D91A/E92A mutant protein was distributed largely to the cytosol, despite myristoylation, suggesting its importance for assistance of membrane localization of TICAM-2. An ectopically expressed D91A/E92A mutant per se failed to activate TICAM-1, unlike its wild-type counterpart that forms self-aggregation, but it still retained the ability to pass LPS-mediated IFN regulatory factor (IRF)3 activation. In a TICAM-2 knockout human cell line expressing TLR4/MD-2 with or without CD14, overexpression of the D91A/E92A mutant did not activate IRF3, but upon LPS stimulation, it induced sufficient TLR4-mediated IRF3 activation with high coefficient colocalization. Hence, the D91/E92 motif guides TICAM-2 membrane localization and self-activation for signaling. Our results suggest the presence of two distinct steps underlying endosomal LPS signaling on TICAM-2 for TICAM-1 activation: TICAM-2 assembling in TLR4 and/or TICAM-2 self-activation. D91A/E92A of TICAM-2 selectively associates the TLR4-dependent TICAM-2 assembling, but not cytosolic TICAM-2 self-aggregation, to activate TICAM-1.

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Selective TRIF-Dependent Signaling by a Synthetic Toll-Like Receptor 4 Agonist

Cited by 71 publications

References 51 publications

Activation of Innate Immune Responses by Haemophilus influenzae Lipooligosaccharide

Activation of Innate Immune Responses by Haemophilus influenzae Lipooligosaccharide

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

Identification of a Regulatory Acidic Motif as the Determinant of Membrane Localization of TICAM-2

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