Long-term activation of TLR3 by Poly(I:C) induces inflammation and impairs lung function in mice

Stowell, Nicole; Seideman, Jonathan; Raymond, Holly; Smalley, Karen; Lamb, Roberta J.; Egenolf, Devon; Bugelski, Peter J.; Murray, Lynne A.; Marsters, P; Bunting, Rachel; Flavell, Richard A.; Alexopoulou, Lena; Mateo, Lani R. San; Griswold, Don E.; Sarisky, Robert T.; Mbow, Moustapha; Das, Anuk

doi:10.1186/1465-9921-10-43

Cited by 154 publications

(140 citation statements)

References 32 publications

(41 reference statements)

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“…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: Discussionsupporting

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).…”

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confidence: 99%

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

Kang

Harten

Chang

et al. 2017

Journal of Biological Chemistry

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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.

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Section: Discussionsupporting

confidence: 55%

mentioning

confidence: 99%

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

Kang

Harten

Chang

et al. 2017

Journal of Biological Chemistry

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“…A large proportion of this signal is expected to be intracellular during viral infections. However, in vitro and in vivo dsRNA administration has been shown to reproduce most of the proinflammatory effect of pulmonary viruses (41). Our data show that the effect of dsRNA on asthma exacerbation is fully TLR3/TRIF dependent.…”

Section: Discussionsupporting

confidence: 50%

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

Torres

Dieudonné

Ryffel

et al. 2010

The Journal of Immunology

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“…These data indicate that SP-C is required to both reduce lung inflammation and enhance resolution of inflammation induced by distinct microbes. In a recent study, sustained TLR3 activation and long-term lung inflammation was achieved using three sequential exposures to double-stranded RNA similar to the current LPS protocol (35). Together, these findings indicate that the infections linked to exacerbations of lung disease in affected individuals may in part be due to recurrent or unremitting signaling by multiple TLR isoforms that include TLR3 and -4.…”

Section: Discussionmentioning

confidence: 85%

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

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Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc 2/2 ) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc 1/1 and Sftpc 2/2 mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc 2/2 mice at 3 and 5 days after the final dose. Compared with Sftpc 1/1 mice, inflammatory injury persisted in the lungs of Sftpc 2/2 mice 30 days after the final LPS challenge. Sftpc 2/2 mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc 2/2 type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc 1/1 cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.Keywords: surfactant protein-C; LPS; lung inflammation; type II cells; Toll-like receptor 4Surfactant protein-C (SP-C) is an abundant 3.5-kD surfactantassociated protein expressed and secreted by alveolar type II epithelial cells. The mature airspace form of SP-C is highly hydrophobic and palmitoylated at adjacent amino terminal cysteine residues (1). Mutations in the gene encoding human SP-C (SFTPC) have been shown to cause familial interstitial lung disease (ILD). Affected individuals express an altered proSP-C, leading to reduced levels of mature SP-C in the airspace (2-4). SP-C deficiencies without detectable mutations in the protein-coding region of SFTPC or due to promoter mutations have also been reported, and represent a true null condition (5-7). These individuals also develop ILD, including idiopathic pulmonary fibrosis (IPF). SP-C deficiency-related disease may arise as an acute childhood or as a late-onset disease in adulthood (3). Because SP-C is expressed exclusively in alveolar type II cells, the associated ILD/idiopathic pulmonary fibrosis presumably originates from a primary defect in the epithelium. SP-C deficiency increases susceptibility to viral-or bacterial-induced exacerbations in affected children (5,6,(8)(9)(10). SP-C-deficient mice (Sftpc 2/2 ) developed a strain-specific pulmonary phenotype with age that was similar to the human disease (11). Sftpc 2/2 mice were more susceptible to challenge with ...

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Long-term activation of TLR3 by Poly(I:C) induces inflammation and impairs lung function in mice

Cited by 154 publications

References 32 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

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

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

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