The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily

Heil, Florian; Ahmad-Nejad, Parviz; Hemmi, Hiroaki; Hochrein, Hubertus; Ampenberger, Franziska; Gellert, Tanja; Dietrich, Harald; Lipford, Grayson B.; Takeda, Kiyoshi; Akira, Shizuo; Wagner, Hermann; Bauer, Stefan

doi:10.1002/eji.200324238

Cited by 501 publications

(397 citation statements)

References 43 publications

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“…TLR7, TLR8, and TLR9 belong to a subfamily of nucleic acid-sensing TLRs. Activation of TLR7, TLR8, and TLR9 in response to their respective ligands depends on acidification and maturation of endosomes and targets MyD88 to vesicular structures with lysosomal characteristics (19). Therefore TLR7, TLR8, and TLR9 form a functional subgroup within the TLR family that recognizes nucleic acids in the acidic environment of an endosome/lysosome.…”

Section: Discussionmentioning

confidence: 99%

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

Doyle

Jefferies

Feighery

et al. 2007

Journal of Biological Chemistry

109

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Toll-like receptors (TLRs) are a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. TLR7 and TLR8 sense single-stranded RNA from viruses or host ribonucleoproteins and synthetic imidazoquinolines such as R848, whereas TLR9 senses unmethylated CpG motifs in viral and bacterial DNA and in host DNA. Here we report the endogenous interaction between Brutons's tyrosine kinase (Btk) and human TLR8 and TLR9 in the monocytic cell line THP1. We also show that R848, single-stranded RNA, and CpGB-DNA activate Btk in THP1 cells as shown by phosphorylation of the tyrosine 223 residue of Btk and also by increased autokinase activity. We demonstrate that Btk is required for NF B activation, participating in the pathway to increased phosphorylation of p65 on serine 536 activated by TLR8 and TLR9. Finally we demonstrate that peripheral blood mononuclear cells from patients with X-linked agammaglobulinaemia (XLA) that have dysfunctional Btk are impaired in the induction of interleukin-6 by CpGB-DNA. This study therefore establishes Btk as a key signaling molecule that interacts with and acts downstream of TLR8 and TLR9. Lack of functioning Btk in XLA patients downstream of TLR8 and TLR9 might explain the susceptibility of XLA patients to viral infections.

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Section: Discussionmentioning

confidence: 99%

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

Doyle

Jefferies

Feighery

et al. 2007

Journal of Biological Chemistry

109

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“…15,16 TLR7 recognizes synthetic imidazoquinoline-like molecules, guanosine analogs such as loxoribine, single-stranded RNA (ssRNA) derived from human immunodeficiency virus type I (HIV-1), vesicular stomatitis virus (VSV) and influenza virus, and certain siRNAs. [17][18][19][20][21][22][23] While mouse TLR8, which shows the highest homology to TLR7, is thought to be nonfunctional, human TLR8 mediates the recognition of imidazoquinolines and ssRNA. [19][20][21] recognizes bacterial and viral CpG DNA motifs and malaria pigment hemozoin.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20][21][22][23] While mouse TLR8, which shows the highest homology to TLR7, is thought to be nonfunctional, human TLR8 mediates the recognition of imidazoquinolines and ssRNA. [19][20][21] recognizes bacterial and viral CpG DNA motifs and malaria pigment hemozoin. [24][25][26][27] After recognition of microbial pathogens, TLRs trigger intracellular signaling pathways that result in the induction of inflammatory cytokines, type I interferon (IFN) and chemokines ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

TLR signaling

2006

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The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-jB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

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“…The imidazoquinoline R848 is a pharmacological immunostimulant that activates the Toll-like receptor 7, which is present in the endosome of myeloid immune cells such as macrophages (Heil et al, 2003). To assess the immune-activating effect of R848 delivered by NP, we determined the amount of the pro-inflammatory cytokine interleukin 6 (IL-6) secreted by J774 macrophages after exposure to R848-NP.…”

Section: R848-loaded Np Activate Macrophagesmentioning

confidence: 99%

“…Imiquimod and resiquimod (R848), two synthetic imidazoquinolines, activate signaling of TLR7 and TLR8 (Heil et al, 2003). These receptors are mainly expressed by monocytes, macrophages and dendritic cells and are localized intracellularly in the endosomal membranes (Nishiya and DeFranco, 2004).…”

Section: Introductionmentioning

confidence: 99%

Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation

Widmer

Thauvin

Mottas

et al. 2018

International Journal of Pharmaceutics

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A B S T R A C TSmall-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to doselimiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DLlactic acid) (mPEG-PLA) and mixed poly(DL-lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles. We show that these particles are taken up mainly by dendritic cells and macrophages, which are the prime initiators of anticancer immune responses. Nanoparticles loaded with resiquimod activate these cells, demonstrating the availability of the immune-stimulating cargo. The unloaded particles are non-inflammatory and do not have cytotoxic activity on immune cells. Following subcutaneous injection in mice, mPEG-PLA and PLGA/mPEG-PLA nanoparticles are detected in dendritic cells and macrophages in the draining lymph nodes, demonstrating the targeting potential of these particles. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy.

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The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily

Cited by 501 publications

References 43 publications

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

TLR signaling

Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation

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