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Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness.

ABSTRACT: Enterovirus D68 (EV-D68) shares biologic features with rhinovirus (RV). In 2014, a nationwide outbreak of EV-D68 was associated with severe asthma-like symptoms. We sought to develop a mouse model of EV-D68 infection and determine the mechanisms underlying airway disease. BALB/c mice were inoculated intranasally with EV-D68 (2014 isolate), RV-A1B, or sham, alone or in combination with anti-IL-17A or house dust mite (HDM) treatment. Like RV-A1B, lung EV-D68 viral RNA peaked 12 hours after infection. EV-D68 induced airway inflammation, expression of cytokines (TNF-?, IL-6, IL-12b, IL-17A, CXCL1, CXCL2, CXCL10, and CCL2), and airway hyperresponsiveness, which were suppressed by anti-IL-17A antibody. Neutrophilic inflammation and airway responsiveness were significantly higher after EV-D68 compared with RV-A1B infection. Flow cytometry showed increased lineage-, NKp46-, ROR?t+ IL-17+ILC3s and ?? T cells in the lungs of EV-D68-treated mice compared with those in RV-treated mice. EV-D68 infection of HDM-exposed mice induced additive or synergistic increases in BAL neutrophils and eosinophils and expression of IL-17, CCL11, IL-5, and Muc5AC. Finally, patients from the 2014 epidemic period with EV-D68 showed significantly higher nasopharyngeal IL-17 mRNA levels compared with patients with RV-A infection. EV-D68 infection induces IL-17-dependent airway inflammation and hyperresponsiveness, which is greater than that generated by RV-A1B, consistent with the clinical picture of severe asthma-like symptoms.

SUBMITTER: Rajput C

PROVIDER: S-EPMC6141171 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness.

Rajput Charu C Han Mingyuan M Bentley J Kelley JK Lei Jing J Ishikawa Tomoko T Wu Qian Q Hinde Joanna L JL Callear Amy P AP Stillwell Terri L TL Jackson William T WT Martin Emily T ET Hershenson Marc B MB

JCI insight 20180823 16

Enterovirus D68 (EV-D68) shares biologic features with rhinovirus (RV). In 2014, a nationwide outbreak of EV-D68 was associated with severe asthma-like symptoms. We sought to develop a mouse model of EV-D68 infection and determine the mechanisms underlying airway disease. BALB/c mice were inoculated intranasally with EV-D68 (2014 isolate), RV-A1B, or sham, alone or in combination with anti-IL-17A or house dust mite (HDM) treatment. Like RV-A1B, lung EV-D68 viral RNA peaked 12 hours after infecti ...[more]

PMID: 30135310

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Project description:BackgroundInterleukin 1 beta (IL-1beta) is found in bronchoalveolar lavage fluids from asthmatic patients and plays an important role in normal immunoregulatory processes but also in pathophysiological inflammatory responses. The present study was designed to investigate if IL-1beta could be involved in the development of airway hyperresponsiveness and if transcriptional mechanisms, epithelium contractile factors and mitogen-activated protein kinase (MAPK) pathways are involved in IL-1beta effect.MethodsThe effect of IL-1beta on 5-hydroxytryptamine (5-HT) induced bronchoconstriction was evaluated in an in-vitro model for assessment of long-term effects of inflammatory mediators on the airway smooth muscle. Murine tracheal segments were cultured up to 8 days in the absence or presence of IL-1beta with subsequent evaluation in a myograph system, along with mRNA quantification, focusing on the role of the epithelium, acetylcholine release, transcriptional mechanisms and MAPK activity.ResultsDuring control conditions, 5-HT induced a relatively weak contraction. Presence of IL-1beta increased this response in a time- and concentration-dependent way. The increased concentration-effect curves could be shifted rightwards in a parallel manner by ketanserin, a selective 5-HT2A receptor antagonist, indicating that the responses are mediated by 5-HT2A receptors. The mRNA levels of 5-HT2A receptors were not changed as a consequence of the IL-1beta treatment and actinomycin D, a general transcriptional inhibitor, failed to affect the contractile response, suggesting a non-transcriptional mechanism behind this phenomenon. Neither the removal of the epithelium nor the addition of atropine affected the IL-1beta induced enhancement of 5-HT2A receptor-mediated contractile response. Application of inhibitors for c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase 1 and 2 (ERK1/2) showed that the signaling pathways for JNK and ERK1/2 dominated only in cultured segments (control) whereas JNK and p38 dominated in segments treated with IL-1beta.ConclusionIL-1beta induces murine airway hyperresponsiveness, via a non-transcriptional up-regulation of 5-HT2A receptor-mediated contractile response. The increase of 5-HT contraction is unrelated to epithelial and cholinergic factors, but is dependent on IL-1beta-induced changes of MAPK pathways. The fact that IL-1beta can alter airway responses to contractile agents such as 5-HT, via alteration of the intracellular MAPK signal transduction pathways, might provide a new concept for future treatment of asthma.

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Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness.

Publications

Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness.

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