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IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation.

ABSTRACT: Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared with OVA or RSV mice alone. Furthermore, interleukin 17A (IL-17A) was only increased in OVA/RSV mice.To determine whether IL-17A increases AR and inflammation in the OVA/RSV model.Wild-type (WT) BALB/c and IL-17A knockout (KO) mice underwent mock, RSV, OVA or OVA/RSV protocols. Lungs, bronchoalveolar lavage (BAL) fluid and/or mediastinal lymph nodes (MLNs) were harvested after infection. Cytokine expression was determined by ELISA in the lungs or BAL fluid. MLNs were restimulated with either OVA (323-229) peptide or RSV M2 (127-135) peptide and IL-17A protein expression was analysed. AR was determined by methacholine challenge.RSV increased IL-17A protein expression by OVA-specific T cells 6 days after infection. OVA/RSV mice had decreased interferon-? protein expression compared with RSV mice. OVA/RSV mice had increased IL-23p19 mRNA expression in lung homogenates compared with mock, OVA or RSV mice. Unexpectedly, IL-17A KO OVA/RSV mice had increased AR compared with WT OVA/RSV mice. Furthermore, IL-17A KO OVA/RSV mice had increased eosinophils, lymphocytes and IL-13 protein expression in BAL fluid compared with WT OVA/RSV mice.IL-17A negatively regulated AR and airway inflammation in OVA/RSV mice. This finding is important because IL-17A has been identified as a potential therapeutic target in asthma, and inhibiting IL-17A in the setting of virally-induced asthma exacerbations may have adverse consequences.

SUBMITTER: Newcomb DC

PROVIDER: S-EPMC3916091 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation.

Newcomb Dawn Catherine DC Boswell Madison G MG Reiss Sara S Zhou Weisong W Goleniewska Kasia K Toki Shinji S Harintho Melissa T MT Lukacs Nicholas W NW Kolls Jay K JK Peebles R Stokes RS

Thorax 20130219 8

<h4>Background</h4>Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared with OVA or RSV mice alone. Furthermore, interleukin 17A (IL-17A) was only increased in OVA/RSV mice.<h4>Objective</h4>To determine whether IL-17A increases AR and inflammation in the OVA/RSV mo ...[more]

PMID: 23422214

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Project description:BACKGROUND:Serum IL-22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2-dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge-induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL-22. OBJECTIVE:We sought to determine the role of IL-22 in antigen-driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. METHODS:Wild-type (WT) and Il22-/- mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T-cell receptor-specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. RESULTS:Epicutaneous sensitization preferentially elicited an IL-22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL-22 production, and accumulation of CD3+CD4+IL-22+ T cells that coexpressed IL-17A and TNF-?. Epicutaneously sensitized Il22-/- mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL-13, IL-17A, and TNF-? was normal, but IFN-? production was increased in lung cells from airway-challenged and epicutaneously sensitized Il22-/- mice. Intranasal instillation of IFN-?-neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22-polarized WT, but not IL-22-deficient, T-cell receptor OVA-specific T cells, which secrete both IL-17A and TNF-?, had neutrophil-dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL-22 with TNF-?, but not IL-17A, elicited neutrophil-dominated airway inflammation and AHR in WT mice, suggesting that loss of IL-22 synergy with TNF-? contributed to defective recruitment of neutrophils into the airways of Il22-/- mice. TNF-?, but not IL-22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. CONCLUSION:Epicutaneous sensitization promotes generation of antigen-specific IL-22-producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL-22 plays an important role in the atopic march.

Dataset Information

IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation.

Publications

IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation.

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