Double-Stranded RNA Exacerbates Pulmonary Allergic Reaction through TLR3: Implication of Airway Epithelium and Dendritic Cells

Torres, David; Dieudonné, Audrey; Ryffel, Bernhard; Vilain, Eva; Si‐Tahar, Mustapha; Pichavant, Muriel; Lassalle, Philippe; Trottein, François; Gosset, Philippe

doi:10.4049/jimmunol.0902833

Cited by 74 publications

(78 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous in vitro studies demonstrated that stimulation of lung fibroblasts with poly(I:C) or other NF-B agonists induces synthesis and accumulation of an HA-enriched ECM serving as a substrate for leukocyte accumulation, including monocytes and T lymphocytes (30, 32, 50 -52). In in vivo studies, poly(I:C) has been used to elicit acute lung inflammation and further exacerbate pulmonary allergic reactions (28,29), which is probably mediated by generating versican-enriched ECM attracting leukocyte accumulation in the inflamed airways, as our data suggest. Further studies are ongoing to elucidate roles of versican in viral exacerbation of asthma.…”

Section: Discussionmentioning

confidence: 55%

“…One of the major inflammatory signaling pathways activated by virus is the Toll-like receptor 3 (TLR3) pathway, which recognizes doublestranded RNA, such as polyinosine-polycytidylic acid (poly(I: C)), and thus is often used as a viral mimetic and a TLR3 agonist. It has been shown to generate an HA-enriched ECM in colon and in kidney, which promotes leukocyte accumulation (23)(24)(25)(26)(27), and has also been shown to elicit acute lung inflammation in vivo and further to exacerbate pulmonary allergic reactions (28,29). A number of studies by our group have demonstrated that lung fibroblasts synthesize and deposit HA-and versican-enriched ECM in response to poly(I:C).…”

mentioning

confidence: 98%

See 1 more Smart Citation

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

Kang

Harten

Chang

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Gerald W. HartViral infection is an exacerbating factor contributing to chronic airway diseases, such as asthma, via mechanisms that are still unclear. Polyinosine-polycytidylic acid (poly(I:C)), a Toll-like receptor 3 (TLR3) agonist used as a mimetic to study viral infection, has been shown to elicit inflammatory responses in lungs and to exacerbate pulmonary allergic reactions in animal models. Previously, we have shown that poly(I:C) stimulates lung fibroblasts to accumulate an extracellular matrix (ECM), enriched in hyaluronan (HA) and its binding partner versican, which promotes monocyte adhesion. In the current study, we aimed to determine the in vivo role of versican in mediating inflammatory responses in poly(I:C)-induced lung inflammation using a tamoxifen-inducible versican-deficient mouse model (Vcan ؊/؊ mice). In C57Bl/6 mice, poly(I:C) instillation significantly increased accumulation of versican and HA, especially in the perivascular and peribronchial regions, which were enriched in infiltrating leukocytes. In contrast, versican-deficient (Vcan ؊/؊ ) lungs did not exhibit increases in versican or HA in these regions and had strikingly reduced numbers of leukocytes in the bronchoalveolar lavage fluid and lower expression of inflammatory chemokines and cytokines. Poly(I:C) stimulation of lung fibroblasts isolated from control mice generated HA-enriched cable structures in the ECM, providing a substrate for monocytic cells in vitro, whereas lung fibroblasts from Vcan ؊/؊ mice did not. Moreover, increases in proinflammatory cytokine expression were also greatly attenuated in the Vcan ؊/؊ lung fibroblasts. These findings provide strong evidence that versican is a critical inflammatory mediator during poly(I:C)-induced acute lung injury and, in association with HA, generates an ECM that promotes leukocyte infiltration and adhesion.

show abstract

Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 98%

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

Kang

Harten

Chang

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…16 TLR3 activation has also been reported to have negative effects in the respiratory tract. 17,18 Influenza infection mediates pathogenic effects in the lungs of wild-type mice, while less tissue damage was detected in TLR3 Ϫ/Ϫ animals. 19 However, damage of the lung does not necessarily have to be because of infection, but can also be enhanced by sterile cell death, for example, during oxygen treatment of patients with acute respiratory distress syndrome.…”

Section: Introductionmentioning

confidence: 99%

Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques

Sköld

Hašan

Vargas

et al. 2012

Blood

View full text Add to dashboard Cite

TLR3 is a key receptor for recognition of double-stranded RNA and initiation of immune responses against viral infections. However, hyperactive responses can have adverse effects, such as virusinduced asthma. Strategies to prevent TLR3-mediated pathology are therefore desired. We investigated the effect of single-stranded DNA oligonucleotides (ssDNA-ODNs) on TLR3 activation. Human monocyte-derived dendritic cells up-regulate maturation markers and secrete proinflammatory cytokines on treatment with the synthetic TLR3 ligand polyinosine-polycytidylic acid (poly I:C). These events were inhibited in cultures with ssDNA-ODNs. Poly I:C activation of nonhematopoietic cells was also inhibited by ssDNA-ODNs. The uptake of poly I:C into cells was reduced in the presence of ssDNA-ODNs, preventing TLR3 engagement from occurring. To confirm this inhibition in vivo, we administered ssDNAODNs and poly I:C, alone or in combination, via the intranasal route in cynomolgus macaques. Proinflammatory cytokines were detected in nasal secretions in the poly I:C group, while the levels were reduced in the groups receiving ssDNA-ODNs or both substances. IntroductionThe immune system distinguishes between self and non-self with a variety of pattern recognition receptors such as Toll-like receptors (TLRs), C-type lectins, RIG-I-like receptors, and Nod-like receptors. [1][2][3][4] Ten genes for TLRs exist in humans and they are expressed on the cellular surface or in the intracellular endosomal compartment. 2 For activation to take place, the receptors form homodimers or heterodimers and transmit a signal via the adaptor proteins MyD88 and/or TIR domain-containing adapter-inducing INF-␤ (TIRF). The extracellular TLRs recognize conserved glycoprotein and lipopeptide structures specific to microbial organisms, while the endosomal receptors recognize nucleic acids. 2 TLR3 is the only receptor transmitting its signal merely via the adaptor protein TRIF and it does so in response to double-stranded RNA (dsRNA) present in, for example, viral genomes or their intermediates during the replication cycle. 5,6 However, selfproduced dsRNA can also engage TLR3 when released from damaged tissues. 7-9 The synthetic ligand polyinosine-polycytidylic acid (poly I:C) is commonly used to target TLR3 in vaccine adjuvant constructs and in different experimental conditions. 4,7,10 Immune activation mediated via TLR3 has been shown to be important in clearance of viral infections because of a robust induction of IL-12 and type I interferons. 5 Furthermore, studies revealing its ability to mediate efficient cross-presentation of endocytosed Ags 11,12 have made TLR3 an interesting target in vaccine adjuvant development. 4,13,14 However, several reports have also implicated TLR3 in having detrimental effects during certain infections or conditions. 5,6 Cells infected with Epstein-Barr virus have been shown to secrete virally encoded RNA detected by TLR3 that results in systemic pathologic immune activation. 15 The role of TLR3 in viral CNS infections is debated, w...

show abstract

“…In turn, such dsRNA motifs can be sensed by the immune system via TLR3 or retinoic acid-inducible gene-I (8,9), suggesting a central role of this receptors in the pathogenesis of acute asthma exacerbations. This hypothesis is supported by mouse experiments demonstrating that not only rhinovirus infection but also local application of viral dsRNA or poly(inosinic-cytidylic) acid (pIC) alone triggers exacerbation of experimental asthma in mice (10)(11)(12). However, the underlying mechanisms of this disease pattern remain completely unclear.…”

mentioning

confidence: 49%

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

Lunding

Webering

Vock

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Viral infection of the respiratory tract represents the major cause of acute asthma exacerbations. dsRNA is produced as an intermediate during replication of respiratory viruses and triggers immune responses via TLR3. This study aimed at clarifying the mechanisms underlying TLR3 triggered exacerbation of experimental allergic asthma. The TLR3 ligand poly(inosinic-cytidylic) acid was applied intranasally to mice with already established experimental allergic asthma. Airway inflammation, cytokine expression, mucus production, and airway reactivity was assessed in wild-type, IL-17A, or IL-23p19–deficient, and in NK cell–depleted mice. Local application of poly(inosinic-cytidylic) acid exacerbated experimental allergic asthma in mice as characterized by enhanced release of proinflammatory cytokines, aggravated airway inflammation, and increased mucus production together with pronounced airway hyperresponsiveness. This was further associated with augmented production of IL-17 by Th17 cells and NK cells. Whereas experimental exacerbation could be induced in IL-23p19–deficient mice lacking mature, proinflammatory Th17 cells, this was not possible in mice lacking IL-17A or in NK cell–depleted animals. These experiments indicate a central role for IL-17 derived from NK cells but not from Th17 cells in the pathogenesis of virus-triggered exacerbation of experimental asthma.

show abstract

Double-Stranded RNA Exacerbates Pulmonary Allergic Reaction through TLR3: Implication of Airway Epithelium and Dendritic Cells

Cited by 74 publications

References 52 publications

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

Contact Info

Product

Resources

About