Raised interferon‐β, type 3 interferon and interferon‐stimulated genes – evidence of innate immune activation in neutrophilic asthma

Silva, J. da; Hilzendeger, Clarissa; Moermans, Catherine; Schleich, Florence; Henket, Monique; Kebadze, Tatiana; Mallia, Patrick; Edwards,; Johnston, Sebastian L.; Louis, Renaud

doi:10.1111/cea.12809

Cited by 40 publications

(32 citation statements)

References 50 publications

(73 reference statements)

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“… 45 On the other hand, a significant heterogeneity of asthma may involve different inflammatory phenotypes, some of which may differ in terms of innate immune activation during viral infection. 46 Our observations documenting impaired IFN responses to viral infection in a subpopulation of asthma patients are in line with well-established non-atopic asthma phenotype, which includes respiratory infections as dominant exacerbation-triggering factors. 47 A recent systematic review documented association of non-atopic asthma/wheeze with lower respiratory tract infections in children and adolescents.…”

Section: Discussionsupporting

confidence: 87%

Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

Moskwa

Piotrowski

Marczak

et al. 2018

Allergy Asthma Immunol Res

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PurposeIn order to gain an insight into determinants of reported variability in immune responses to respiratory viruses in human bronchial epithelial cells (HBECs) from asthmatics, the responses of HBEC to viral infections were evaluated in HBECs from phenotypically heterogeneous groups of asthmatics and in healthy controls.MethodsHBECs were obtained during bronchoscopy from 10 patients with asthma (6 atopic and 4 non-atopic) and from healthy controls (n=9) and grown as undifferentiated cultures. HBECs were infected with parainfluenza virus (PIV)-3 (MOI 0.1) and rhinovirus (RV)-1B (MOI 0.1), or treated with medium alone. The cell supernatants were harvested at 8, 24, and 48 hours. IFN-α, CXCL10 (IP-10), and RANTES (CCL5) were analyzed by using Cytometric Bead Array (CBA), and interferon (IFN)-β and IFN-λ1 by ELISA. Gene expression of IFNs, chemokines, and IFN-regulatory factors (IRF-3 and IRF-7) was determined by using quantitative PCR.ResultsPIV3 and RV1B infections increased IFN-λ1 mRNA expression in HBECs from asthmatics and healthy controls to a similar extent, and virus-induced IFN-λ1 expression correlated positively with IRF-7 expression. Following PIV3 infection, IP-10 protein release and mRNA expression were significantly higher in asthmatics compared to healthy controls (median 36.03-fold). No differences in the release or expression of RANTES, IFN-λ1 protein and mRNA, or IFN-α and IFN-β mRNA between asthmatics and healthy controls were observed. However, when asthmatics were divided according to their atopic status, HBECs from atopic asthmatics (n=6) generated significantly more IFN-λ1 protein and demonstrated higher IFN-α, IFN-β, and IRF-7 mRNA expressions in response to PIV3 compared to non-atopic asthmatics (n=4) and healthy controls (n=9). In response to RV1B infection, IFN-β mRNA expression was lower (12.39-fold at 24 hours and 19.37-fold at 48 hours) in non-atopic asthmatics compared to atopic asthmatics.ConclusionsThe immune response of HBECs to virus infections may not be deficient in asthmatics, but seems to be modified by atopic status.

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Section: Discussionsupporting

confidence: 87%

Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

Moskwa

Piotrowski

Marczak

et al. 2018

Allergy Asthma Immunol Res

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“…Neutrophil functions are crucial in clearing bacterial infections and wound repair (175,176). A major target of the effects of IFN-λs may be neutrophils (62,177). A study by Blazek et al showed that in a collagen-induced arthritis model, IFNL1 showed anti-inflammatory function by reducing the numbers of IL17producing Th17 cells and the recruitment of IL-1b expressing neutrophils, which is important to amplify the inflammatory process (62).…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Interferon Lambda: Modulating Immunity in Infectious Diseases

2017

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Interferon lambdas (IFN-λs; IFNL1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. IFN-λs act by binding to the heterodimeric IFN-λ receptor (IFNLR), activating a STAT phosphorylation-dependent signaling cascade. Thereby hundreds of IFN-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. When compared to the well-characterized IFN-α signaling cascade, three important differences have been discovered. First, the IFNLR is not ubiquitously expressed: in particular, immune cells show significant variation in the expression levels of and susceptibilities to IFN-λs. Second, the binding affinities of individual IFN-λs to the IFNLR varies greatly and are generally lower compared to the binding affinities of IFN-α to its receptor. Finally, genetic variation in the form of a series of single-nucleotide polymorphisms (SNPs) linked to genes involved in the IFN-λ signaling cascade has been described and associated with the clinical course and treatment outcomes of hepatitis B and C virus infection. The clinical impact of IFN-λ signaling and the SNP variations may, however, reach far beyond viral hepatitis. Recent publications show important roles for IFN-λs in a broad range of viral infections such as human T-cell leukemia type-1 virus, rotaviruses, and influenza virus. IFN-λ also potentially modulates the course of bacterial colonization and infections as shown for Staphylococcus aureus and Mycobacterium tuberculosis. Although the immunological processes involved in controlling viral and bacterial infections are distinct, IFN-λs may interfere at various levels: as an innate immune cytokine with direct antiviral effects; or as a modulator of IFN-α-induced signaling via the suppressor of cytokine signaling 1 and the ubiquitin-specific peptidase 18 inhibitory feedback loops. In addition, the modulation of adaptive immune functions via macrophage and dendritic cell polarization, and subsequent priming, activation, and proliferation of pathogen-specific T- and B-cells may also be important elements associated with infectious disease outcomes. This review summarizes the emerging details of the IFN-λ immunobiology in the context of the host immune response and viral and bacterial infections.

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“…However, rhinovirus-induced interferon production in hBECs is not deficient in well-controlled asthma (Sykes et al, 2014), hBECs from asthmatics have preserved interferon responses to influenza and respiratory syncytial virus (RSV) (Patel et al, 2014), and TLR responses are not impaired in asthmatic airway and blood cells (Sykes et al, 2013). In addition, robust IFN-γ and IFN-λ responses have been found clinically in children with asthma during naturally-occurring virus-induced exacerbations (Lewis et al, 2012, Miller et al, 2012), and severe adult asthmatics and neutrophilic asthmatics have recently been shown to have a dominant IFN-γ immune response in BAL (Raundhal et al, 2015, da Silva et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13)

et al. 2017

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BackgroundRhinovirus infection is a major cause of asthma exacerbations.ObjectivesWe studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations.MethodsWe used nasosorption on days 0, 2–5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n = 28) and healthy non-atopic controls (n = 11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay.ResultsFollowing rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P < 0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0–7, all P < 0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P < 0.01) and levels increased by days 3 and 4 (P < 0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7 days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P < 0.05).ConclusionsPrecision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation.

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Raised interferon‐β, type 3 interferon and interferon‐stimulated genes – evidence of innate immune activation in neutrophilic asthma

Abstract: Running TitleRaised interferons β and λ in neutrophilic asthma Accepted ArticleThis article is protected by copyright. All rights reserved.

Cited by 40 publications

References 50 publications

Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

Interferon Lambda: Modulating Immunity in Infectious Diseases

A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13)

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