Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA

Diebold, Sandra S.; Kaisho, Tsuneyasu; Hemmi, Hiroaki; Akira, Shizuo; Sousa, Caetano Reis e

doi:10.1126/science.1093616

Cited by 2,986 publications

(2,415 citation statements)

References 26 publications

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“…Rejman et al demonstrated that both lipid-based carriers, such as DOTAP/DOPE, and polymers, exemplified by poly-ethylene-imine (PEI) are capable of transfecting mRNA into cells with a higher and longer lasting protein expression found for liposomes than for polymers (the reason being currently unknown) [75]. As for the protamine-RNA complexes, also DOTAP and PEI RNA formulations were shown to be detected by TLR-7 and TLR-8 [26,30]. Furthermore, Lonez et al conclude that multiple cationic lipids, such as stearylamine-liposomes and Lipofectamine, in itself activate intracellular immune pathways, independent of mRNA complexation, resulting in the induction of several pro-apoptotic and pro-inflammatory signaling molecules [76].…”

Section: Mrna Delivery Methodsmentioning

confidence: 99%

“…As such, especially uridine-rich ssRNA was identified as a strong immune inducer, mainly via stimulation of TLR7 [26,27], whereas dsRNA rather activates TLR3 [28,29]. Generally, mRNA is considered ssRNA, causing the foreign IVT mRNA to be mostly recognized by the structurally homologous TLR7 and TLR8 receptors [26,30]. However, mRNA is also able to form secondary structures, such as hairpins, containing double stranded sequences.…”

Section: In Vitro Transcribed (Ivt) Mrnamentioning

confidence: 99%

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Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Devoldere

Dewitte

Smedt

2016

Drug Discovery Today

110

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Teaser:This review presents an overview of the immune-related hurdles that limit mRNA advance for non-immunotherapy related applications and suggest some promising methods to reduce this 'unwanted' innate immune response. Author photographs and biographiesJoke Devoldere (1990) Her project lies on the interface between material science and immunology as it aims to develop novel micro-and nanomaterials for the delivery of antigen-coding mRNA to induce antitumor immunity. With her research, she won several awards, among which the "Therapeutic use of microbubbles" oral presentation award (Rotterdam, The Netherlands) and the Jan Feijen poster prize at the 13 th European symposium on controlled drug delivery (Egmond aan Zee, The Netherlands). Evading innate immunity in non-viral mRNA delivery: don't shoot the messenger AbstractIn de field of non-viral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known the introduction of IVT mRNA into mammalian cells elicits an innate immune response which has favored mRNA use towards immunotherapeutic vaccination strategies. However, for non-immunotherapy related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, as it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy related applications.

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Section: Mrna Delivery Methodsmentioning

confidence: 99%

Section: In Vitro Transcribed (Ivt) Mrnamentioning

confidence: 99%

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Devoldere

Dewitte

Smedt

2016

Drug Discovery Today

110

View full text Add to dashboard Cite

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“…TLR 7/9 are expressed by both human and mouse PDC 7, 36 . These two endoplasmic TLRs allow PDC to recognize cytosine-phosphate guanosine (CpG)-rich unmethylated DNA from bacteria and DNA viruses, 7, 31, 37 , as well as viral single-stranded RNA (ssRNA), 31, 38, 39 , respectively. In addition, PDC are able to recognize via TLR7/9 mammalian nucleic acids 40 , in particular when these nucleic acids are complexed or associated with antimicrobial peptides (e.g., LL37) 41, 42 .…”

Section: The Innate Immune Functions Of Plasmacytoid Dendritic Cellsmentioning

confidence: 99%

“…These data have been confirmed in vivo using live attenuated viral yellow fever vaccine 79 . The virus responsible for yellow fever is an ssRNA virus and TLR7 recognizes ssRNA 38 . Rapamycin may act at two levels: i ) by inactivating via the inhibition of 4E-BP phosphorylation the nuclear translocation of IRF7 required for type I IFN gene transcription; and ii ) by blocking the formation of the TLR9-MyD88 complex via the p70 ribosomal S6 kinase 1 78 .…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

“…The exposure of human PDC to two different ssRNA viruses, influenza virus (Flu) and Rhinovirus (RV) – triggering the TLR7 pathway via ssRNA recognition 38 – activates HIF-1α 4 , a major regulator of metabolism ( Figure 2A). Indeed, HIF-1α is critical for glycolysis to generate ATP, since it induces the expression of different glycolytic enzymes, such as hexokinase and phosphofructokinase 80 .…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

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Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Saas¹,

Varin²,

Perruche³

et al. 2017

F1000Res

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There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors ( i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

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Psoriasis Triggered by Toll-like Receptor 7 Agonist Imiquimod in the Presence of Dermal Plasmacytoid Dendritic Cell Precursors

Gilliet¹,

Conrad²,

Geiges³

et al. 2004

Arch Dermatol

358

286

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Background: It has been proposed that the innate immune system plays a central role in driving the autoimmune T-cell cascade leading to psoriasis; however, there is no direct evidence for this. Observations:We observed aggravation and spreading of a psoriatic plaque when treated topically with the toll-like receptor (TLR) 7 agonist imiquimod. The exacerbation of psoriasis was accompanied by a massive induction of lesional type I interferon activity, detected by MxA expression after imiquimod therapy. Since imiquimod induces large amounts of type I interferon production from TLR7-expressing plasmacytoid dendritic cell precursors (PDCs), the natural interferon-producing cells of the peripheral blood, we asked whether PDCs are pres-ent in psoriatic skin. We identified high numbers of PDCs in psoriatic skin lesions (up to 16% of the total dermal infiltrate) based on their coexpression of BDCA2 and CD123. By contrast, PDCs were present at very low levels in atopic dermatitis and not detected in normal human skin. Conclusions:This study shows that psoriasis can be driven by the innate immune system through TLR ligation. Furthermore, our finding that large numbers of PDCs infiltrate psoriatic skin suggests a role of lesional PDCs as type I interferon-producing targets for the TLR7 agonist imiquimod.

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Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA

Cited by 2,986 publications

References 26 publications

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Psoriasis Triggered by Toll-like Receptor 7 Agonist Imiquimod in the Presence of Dermal Plasmacytoid Dendritic Cell Precursors

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