Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia

Hatchwell, Luke, Collison, Adam, Girkin, Jason, Parsons, Kristy, Li, Junyao, Zhang, Jie, Phipps, Simon, Knight, Darryl, Bartlett, Nathan W., Johnston, Sebastian L., Foster, Paul S., Wark, Peter A. B. and Mattes, Joerg (2015) Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia. Thorax, 70 9: 854-861. doi:10.1136/thoraxjnl-2014-205465


Author Hatchwell, Luke
Collison, Adam
Girkin, Jason
Parsons, Kristy
Li, Junyao
Zhang, Jie
Phipps, Simon
Knight, Darryl
Bartlett, Nathan W.
Johnston, Sebastian L.
Foster, Paul S.
Wark, Peter A. B.
Mattes, Joerg
Title Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia
Journal name Thorax   Check publisher's open access policy
ISSN 0040-6376
1468-3296
Publication date 2015-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1136/thoraxjnl-2014-205465
Open Access Status Not yet assessed
Volume 70
Issue 9
Start page 854
End page 861
Total pages 8
Place of publication London, United Kingdom
Publisher BMJ Group
Language eng
Subject 2740 Pulmonary and Respiratory Medicine
Abstract Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood. Objectives To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection. Methods Wild-Type and TLR7-deficient (Tlr7?/?) BALB/ c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells ( pDC). Results Allergic Tlr7?/? mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFN? release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-To-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFN?2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils. Conclusions This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophiltargeting treatments for the prevention of asthma exacerbations.
Formatted abstract
Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood.

Objectives To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection.

Methods Wild-type and TLR7-deficient (Tlr7−/−) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC).

Results Allergic Tlr7−/− mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFNγ release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFNλ2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils.

Conclusions This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations.
Keyword Respiratory System
Respiratory System
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 1011153
455623
06-050
G1000758
233015
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Biomedical Sciences Publications
 
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