Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses

Forsbach, Alexandra; Némorin, Jean-Guy; Montino, Carmen; Müller, Christian; Samulowitz, Ulrike; Vicari, Alain; Jurk, Marion; Mutwiri, George; Krieg, Arthur Μ.; Lipford, Grayson B.; Vollmer, Jörg

doi:10.4049/jimmunol.180.6.3729

Cited by 266 publications

(280 citation statements)

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“…Furthermore, speciesspecific variation in PolyU-mediated TLR8 activation has previously been described in immune cells (40,41). PolyU activated TLR8 in human and bovine leukocytes but failed to activate TLR8 on immune cells in mice and rats (39). Our findings are consistent with these data.…”

Section: Discussionsupporting

confidence: 83%

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Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.Keywords: Toll-like receptor 7; imiquimod; nitric oxide; asthma; nerve Toll-like receptor (TLR) 7 is a pattern recognition receptor in the lungs (1-3) that detects single-stranded RNA genomes, common to many respiratory viruses (4). Respiratory viruses cause airway hyperreactivity (an abnormal tendency to contract) (5, 6) and asthma exacerbations (7). A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10). Furthermore, in mouse models of allergic airway inflammation, the TLR7 imidazoquinoline agonists imiquimod (R837) and resiquimod (R848) reduced airway hyperreactivity, airway eosinophilia, goblet cell hyperplasia, and smooth muscle hypertrophy (11-14), whereas TLR7 knockout mice were prone to the development of asthma-like airway pathology after pneumovirus infection (15). These studies suggest that TLR7 may be protective against the development of allergic type 2 T-helper cell airway inflammation, possibly by altering the Th1 versus Th2 immune balance (16). Similarly, a TLR7 agonist is currently i...

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Section: Discussionsupporting

confidence: 83%

“…preferentially activate TLR8 and not TLR7 (39). Although less is known about TLR8, it is highly homologous to TLR7 and similarly recognizes single-stranded RNA.…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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“…(27). It has been reported that 29-O methylation of any nucleotide in ssRNA can abrogate its immunostimulatory effect (28) and, as a result of higher receptor affinity, can compete with other immunostimulatory ssRNAs for TLR7 binding (29).…”

Section: Mapping Of Endosomal Rna Sensors Highlights the Role Of Tlr7mentioning

confidence: 99%

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

Pepini

Pulichino

Carsillo

et al. 2017

The Journal of Immunology

170

162

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RNA-based vaccines have recently emerged as a promising alternative to the use of DNA-based and viral vector vaccines, in part because of the potential to simplify how vaccines are made and facilitate a rapid response to newly emerging infections. SAM vaccines are based on engineered self-amplifying mRNA (SAM) replicons encoding an Ag, and formulated with a synthetic delivery system, and they induce broad-based immune responses in preclinical animal models. In our study, in vivo imaging shows that after the immunization, SAM Ag expression has an initial gradual increase. Gene expression profiling in injection-site tissues from mice immunized with SAM-based vaccine revealed an early and robust induction of type I IFN and IFN-stimulated responses at the site of injection, concurrent with the preliminary reduced SAM Ag expression. This SAM vaccine-induced type I IFN response has the potential to provide an adjuvant effect on vaccine potency, or, conversely, it might establish a temporary state that limits the initial SAM-encoded Ag expression. To determine the role of the early type I IFN response, SAM vaccines were evaluated in IFN receptor knockout mice. Our data indicate that minimizing the early type I IFN responses may be a useful strategy to increase primary SAM expression and the resulting vaccine potency. RNA sequence modification, delivery optimization, or concurrent use of appropriate compounds might be some of the strategies to finalize this aim.

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“…TLR7 is expressed in human B cells and plasmacytoid dendritic cells (4) and TLR8 is expressed in human monocytes and myeloid dendritic cells (8,9). Wide use of synthetic RNA as agonists of TLR7 and TLR8 has been hampered by their susceptibility to nuclease degradation (10)(11)(12), and lipid carriers have been needed for in vitro and in vivo studies (8,(11)(12)(13). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immune-modulatory RNA (SIMRA) compounds (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Wang

Precopio

Lan

et al. 2010

Molecular Cancer Therapeutics

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Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immunemodulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4 + CD25 + Foxp3 + T regulatory cells and a significant increase in tumor antigen-specific IFN-γ-secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9 −/− mice, but not in TLR7 −/− and MyD88 −/− mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway. Mol Cancer Ther; 9(6); 1788-97. ©2010 AACR.

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Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses

Cited by 266 publications

References 54 publications

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

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