Type-I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors

Foronjy, Robert; Taggart, Clifford C.; Dabo, Abdoulaye; Weldon, Sinéad; Cummins, Neville; Geraghty, Patrick

doi:10.1038/mi.2014.54

Cited by 31 publications

(40 citation statements)

References 46 publications

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“…The inhibition of MMP-12 obviously attenuated long-term airway inflammation and AHR, suggesting that MMP-12 was involved in long-term airway diseases induced by RSV infection. This result advanced our previous study and reports of others, which mainly found that MMP-12 was associated with acute airway inflammation and AHR after RSV infection (11,37). Furthermore, the level of MMP-12 was decreased in PCFdegenerated mice infected with RSV.…”

Section: Discussionsupporting

confidence: 80%

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Zang

Zhuang

Deng

et al. 2016

J Virol

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Children with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders. IMPORTANCEThe current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibition of PCF activity can be targeted therapeutically for virus infection-induced long-term airway disorders. R espiratory syncytial virus (RSV) remains the leading cause of viral bronchiolitis and pneumonia in infants and young children throughout the world. Among the 1% to 3% of infants hospitalized with RSV bronchiolitis, up to 90% of children have experience 2 or more wheezing episodes, and almost 50% will be given a diagnosis of asthma by the age of 6 years (1, 2). Several studies, including epidemiology studies and animal model studies, have shown that RSV persistence in the lung of the host after RSV infection was related to long-term airway hyperresponsiveness (AHR) and inflammation (3-5). However, the mechanisms of these sequelae are poorly understood.We have reported that enhanced NGF (nerve growth factor) was partially involved in long-term airway inflammation and AHR after RSV infection (6), suggesting that neurogenic factors participate in long-term airway diseases. Eleva...

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Section: Discussionsupporting

confidence: 80%

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Zang

Zhuang

Deng

et al. 2016

J Virol

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“…[12] More recently, it was shown that known PAR-1 activating proteases, such as MMP1 and MMP13, are highly expressed in respiratory syncytial virus infected mouse lungs and infected human lung epithelial cells in vitro. [44] Here, we showed that thrombin is one of the possible activators of PAR-1 after poly I:C injections. Inhibition of thrombin during in vivo poly I:C stimulation resulted in reduced IFNβ and IFNβ-response gene expression in the spleen and plasma.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice

Antoniak¹,

Tatsumi²,

Bode³

et al. 2016

J Innate Immun

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The coagulation cascade is activated during viral infections as part of the host defense system. Coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). Recently, we reported that the activation of PAR-1 enhanced interferon (IFN)β and CXCL10 expression in cardiac fibroblasts and in the hearts of mice infected with Coxsackievirus B3. In this study, we used the double-stranded RNA mimetic polyinosinic:polycytidylic acid (poly I:C) to induce an antiviral response in macrophages and mice. Activation of PAR-1 enhanced poly I:C induction of IFNβ and CXCL10 expression in the murine macrophage cell line RAW264.7, bone-marrow derived mouse macrophages (BMM) and mouse splenocytes. Next, poly I:C was used to induce a type I IFN innate immune response in the spleen and plasma of wild-type (WT) and PAR-1^-/- mice. We found that poly I:C treated PAR-1^-/- mice and WT mice given the thrombin inhibitor dabigatran etexilate exhibited significantly less IFNβ and CXCL10 expression in the spleen and plasma than WT mice. These studies suggest that thrombin activation of PAR-1 contributes to the antiviral response in mice.

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“…Mmp-9 expression in lung macrophages is induced via the TLR7/NF-κB pathway in IAV-infected mice (31). Interestingly, Mmp-9 expression was increased in murine lungs and human small airway epithelial cells infected with respiratory syncytial virus (RSV) via the type I IFN pathway and RIG-I-like receptors (32). Thus, the increases in lung type I IFN levels detected on day 3 p.i.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection

Rojas¹,

Wang²,

Tipper³

et al. 2018

JCI Insight

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Type-I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors

Cited by 31 publications

References 46 publications

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice

Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection

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