Rhinovirus 16–induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients

Sykes, Annemarie; Edwards, Michael R.; Macintyre, Jonathan; Rosario, Ajerico Del; Bakhsoliani, Eteri; Trujillo-Torralbo, Maria Belen; Kon, Onn Min; Mallia, Patrick; McHale, Mark; Johnston, Sebastian L.

doi:10.1016/j.jaci.2012.03.044

Cited by 188 publications

(222 citation statements)

References 35 publications

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“…However, there is a lack of consistency in the literature, with reports that IFN production by asthmatic fibroblasts (36), peripheral blood mononuclear cells (9), and epithelial cells from patients with well-controlled asthma (37) is adequate. We demonstrate that in patients with SA, AMs have impaired RV-induced IFN responses.…”

Section: Discussionmentioning

confidence: 99%

“…Reduced in SA-AM BAL cells from patients with nonsevere asthma have been shown to have impaired RV-induced IFN responses (7,9), and we first set out to confirm that SA-AMs have a similar deficiency. The expression of IFN-b and IFN-a mRNA and protein levels were measured 24 hours after ex vivo stimulation of healthy subjects and patients with SA-AM with RV16, UV-RV (ultraviolet-inactivated RV16), or medium alone.…”

Section: Tlr7 Expression and Function Ismentioning

confidence: 96%

“…Previous work has shown that bronchoalveolar lavage (BAL) cells (which are predominantly AMs) from individuals with nonsevere asthma have a deficient IFN response to RV infection (7,9); TLR7 function has been shown to be impaired in the peripheral blood mononuclear cells of patients with asthma (20). Therefore, we hypothesized that reduced TLR7-derived signaling drove the impaired IFN responses to RV by the AMs in patients with asthma.…”

mentioning

confidence: 96%

“…This vulnerability is believed to be caused by an impaired IFN response to virus (7)(8)(9)(10). IFN is an antiviral cytokine, and its production is triggered when pattern recognition receptors (PRRs) are activated by viral genomic material (11).…”

mentioning

confidence: 99%

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Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

Rupani

Martínez-Nuñez

Dennison

et al. 2016

Am J Respir Crit Care Med

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Rationale: Asthma is one of the most common chronic diseases worldwide, and individuals with severe asthma experience recurrent exacerbations. Exacerbations are predominantly viral associated and have been linked to defective airway IFN responses. Ascertaining the molecular mechanisms underlying this deficiency is a major research goal to identify new therapeutic targets.Objectives: We investigated the hypothesis that reduced Toll-like receptor 7 (TLR7)-derived signaling drove the impaired IFN responses to rhinovirus by asthmatic alveolar macrophages (AMs); the molecular mechanisms underlying this deficiency were explored.Methods: AMs were recovered from bronchoalveolar lavage from healthy subjects and patients with severe asthma. Expression of pattern-recognition receptors and microRNAs was evaluated by quantitative polymerase chain reaction and Western blotting. A TLR7-luciferase reporter construct was created to evaluate binding of microRNAs to the 39 untranslated region of TLR7. IFN production was measured by quantitative polymerase chain reaction and ELISA.Measurements and Main Results: The expression of TLR7 was significantly reduced in severe asthma AMs and was associated with reduced rhinovirus and imiquimod-induced IFN responses by these cells compared with healthy AMs. Severe asthma AMs also expressed increased levels of three microRNAs, which we showed were able to directly reduce TLR7 expression. Ex vivo knockdown of these microRNAs restored TLR7 expression with concomitant augmentation of virus-induced IFN production.Conclusions: In severe asthma, TLR7 deficiency drives impaired innate immune responses to virus by AMs. Blocking a group of microRNAs that are up-regulated in these cells can restore antiviral innate responses, providing a novel approach for therapy in asthma.

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Section: Discussionmentioning

confidence: 99%

Section: Tlr7 Expression and Function Ismentioning

confidence: 96%

mentioning

confidence: 96%

mentioning

confidence: 99%

See 2 more Smart Citations

Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

Rupani

Martínez-Nuñez

Dennison

et al. 2016

Am J Respir Crit Care Med

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“…Following prolonged allergen avoidance, ongoing asthma symptoms are associated with persistently lower pDC expression of the ligand for the regulatory protein known as inducible costimulatory molecule (ICOS-L). Blood mononuclear cells from those with asthma generally produce less IFNα following viral activation in vitro; this appears to be most evident in those with severe asthma 31,33 and airway neutrophilia 34 , but may not be seen in milder asthma 35 . Deficient IFN production by blood leukocytes in asthma is likely to be a consequence of pDC dysfunction, though only a few studies have specifically examined purified pDC.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Dendritic Cells in Human Lung Disease

Upham

Yang

2017

CHEST

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Impaired interferon‐α expression in plasmacytoid dendritic cells in asthma

Lin

Tsao

et al. 2020

Immunity Inflam & Disease

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Background Toll‐like receptor (TLR)‐7‐associated rhinovirus (RV) activation is involved in the pathogenesis of asthma. Plasmacytoid dendritic cells (pDCs) are the main interferon‐α‐producing cells against viruses. Objective To determine whether asthmatic patients and control subjects differ in terms of interferon‐α expression in pDCs under TLR‐7 or RV stimulation. Methods pDCs were identified in BDCA‐2+ and HLA‐DR+ peripheral blood mononuclear cells. Interferon‐α expression of pDCs was analyzed after TLR‐7 stimulation with or without interleukin 4 (IL‐4)/IL‐13 pretreatment. Interferon‐α expression was also analyzed after RV stimulation over periods of 24, 48, or 96 h with or without IL‐4 pretreatment. RV detection and molecular typing were assayed from throat swabs. Results Following TLR‐7 stimulation, the expression of intracellular interferon‐α was higher in the pDCs of normal subjects than those of asthmatic patients; however, pretreatment with IL‐4 was shown to reduce this effect. After 48‐ and 96‐h RV stimulation, we observed a notable increase in the production of interferon‐α of pDCs in normal subjects but not in asthmatic patients. Baseline interferon‐α expression in pDCs and the incidence of asthma exacerbation to emergency was higher among the 13% of patients identified as rhinovirus+ than among their RV counterparts. Conclusion Our study discovered the response to TLR‐7 stimulation in pDCs was compromised and the sustainability of interferon‐α expression to RV stimulation was reduced in pDCs of asthmatic patients, which provide further evidence of defective innate response and subspeciality to RV infection in asthma. The high exacerbation history founded in RV+ patients agrees with these findings. Further research is required for the modulatory effect of IL‐4 on TLR‐7 stimulated pDCs.

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Rhinovirus 16–induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients

Cited by 188 publications

References 35 publications

Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

Dendritic Cells in Human Lung Disease

Impaired interferon‐α expression in plasmacytoid dendritic cells in asthma

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