Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

BackgroundAsthma 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.ObjectivesTo 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.MethodsWild-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).ResultsAllergic 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.ConclusionsThis 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.

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“…Single lung cell suspensions were prepared and stained as previously described 18. Antibodies used were FITC-anti-TCRβ chain (BD, cat.…”

Section: Methodsmentioning

confidence: 99%

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

Hatchwell

Collison

Girkin

et al. 2015

Thorax

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“…AHR was measured as previously described (13)(14)(15). Briefly, mice were anesthetized with ketamine-xylene combination (Illum) and total lung resistance and dynamic compliance were measured invasively (Buxco).…”

Section: Ahr Measurementmentioning

confidence: 99%

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection

Girkin

Hatchwell

Foster

et al. 2015

The Journal of Immunology

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Rhinovirus infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B (RV1B) infected naïve BALB/c mice (non-allergic) and identified CCL7 and IRF7 amongst the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 antibodies and an IRF7-targeting small interfering RNA in vivo. Neutralising CCL7 or inhibiting IRF7 limited neutrophil and macrophage influx and IFN responses in non-allergic mice. Neutralising CCL7 also reduced activation of NF-κB p65 and p50 subunits, as well as airways hyperreactivity (AHR) in non-allergic mice. However, neither NF-κB subunit activation nor AHR were abolished with infection of allergic mice after neutralising CCL7, despite a reduction in the number of neutrophils, macrophages and eosinophils. IRF7 siRNA primarily suppressed IFN-α and -β levels during infection of allergic mice. Our data highlight a pivotal role of CCL7 and IRF7 in RV-induced inflammation and IFN responses and link NF-κB signalling to the development of AHR.

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“…186 Treatment with a nontoxic anthraquinone derivate reduced RV-induced AHR, neutrophil, and eosinophil airway inflammation; inflammatory cytokine production; and mucus hypersecretion while also boosting type 1 IFN response and reducing viral yields, with associated decreased AKT, HIF-1α, and VEGF production. 187 Treatment with an antiinflammatory VAP-1/SSAO inhibitor, PXS-4728A, or the macrolide antibiotic azithromycin also reduced neutrophil numbers and PXS-4728A reduced AHR following RV-A1 inoculation in HDM-allergic mice. 188 8.11.2 Mouse chronic obstructive pulmonary disease exacerbation models RV also plays an important role in virus-induced exacerbations of COPD.…”

Section: Mouse Asthma Exacerbation Modelsmentioning

confidence: 94%

In vivo experimental models of infection and disease

Girkin

Maltby

Singanayagam

et al. 2019

Rhinovirus Infections

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Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

Cited by 17 publications

References 64 publications

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

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

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection

In vivo experimental models of infection and disease

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